==== Front Mol Cancer Mol Cancer Molecular Cancer 1476-4598 BioMed Central London 1810 10.1186/s12943-023-01810-1 Review Epigenetic modification of m6A regulator proteins in cancer Wang Yumin 1 Wang Yan 2 Patel Harsh 3 Chen Jichao 1 Wang Jinhua wjh@imm.ac.cn 4 Chen Zhe-Sheng chenz@stjohns.edu 3 Wang Hongquan whongquan@alu.fudan.edu.cn 5 1 grid.11135.37 0000 0001 2256 9319 Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049 China 2 grid.452708.c 0000 0004 1803 0208 Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410008, China 3 grid.264091.8 0000 0001 1954 7928 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439 USA 4 grid.506261.6 0000 0001 0706 7839 Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China 5 grid.411918.4 0000 0004 1798 6427 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 China 30 6 2023 30 6 2023 2023 22 1024 4 2023 19 6 2023 © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Divergent N6-methyladenosine (m6A) modifications are dynamic and reversible posttranscriptional RNA modifications that are mediated by m6A regulators or m6A RNA methylation regulators, i.e., methyltransferases (“writers”), demethylases (“erasers”), and m6A-binding proteins (“readers”). Aberrant m6A modifications are associated with cancer occurrence, development, progression, and prognosis. Numerous studies have established that aberrant m6A regulators function as either tumor suppressors or oncogenes in multiple tumor types. However, the functions and mechanisms of m6A regulators in cancer remain largely elusive and should be explored. Emerging studies suggest that m6A regulators can be modulated by epigenetic modifications, namely, ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, in cancer. This review summarizes the current roles of m6A regulators in cancer. The roles and mechanisms for epigenetic modification of m6A regulators in cancer genesis are segregated. The review will improve the understanding of the epigenetic regulatory mechanisms of m6A regulators. Keywords Cancer N6-methyladenosine methylation RNA modification m6A regulators m6A methylation enzymes Science Foundation of CASIC2020-LCYL-009 Hygiene and Health Development Scientific Research Fostering Plan of Haidian District BeijingHP2021-19-50701 Science Foundation of ASCHYN202104 Science Foundation of AMHT2022YK01 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2023 ==== Body pmcBackground Similar to DNA and proteins, RNA can undergo more than 170 post-transcriptional modifications [1]. In the 1970s, adenosine, an RNA building block, was demonstrated to be methylated at N6 nitrogen atom (i.e., N6-methyladenosine (m6A) formation) [2, 3]. Consequently, m6A modification has been identified as the most abundant cellular modification in mammalian mRNA. A pioneer study demonstrated, for the first time, role of m6A in mRNA stability [4], followed by cloning and discovery (in 1997) of methyltransferase-like protein 3 (METTL3), which synthesizes nearly all m6A in the mRNA transcriptome (Fig. 1) [5]. In addition, other studies have shown that m6A is essential for regulation of many developmental processes [6, 7]. This has resulted in rapid development of detection and transcriptome-wide mapping technologies for m6A-containing transcripts, enabling detection in nearly all types of RNAs, including mRNAs, small nuclear RNAs (snRNAs), ribosomal RNAs (rRNAs), and several species of regulatory RNAs [8]. Previous studies have largely focused on delineating the role of m6A methylation in mRNA metabolism and tumor progression; however, emerging evidence has revealed that m6A is involved in almost all RNA metabolic processes, such as mRNA maturation, transcription, translation, degradation, and stability. Dysregulation of m6A results in pathogenesis of multiple human diseases, including cancer. Growing evidence suggests m6A alteration is involved in tumorigenesis through many regulatory mechanisms in programmed cell death [9], metabolism [10], drug resistance [11], oncogene and/or tumor suppressor expression [12], immunotherapy [13], and targeted therapy [14]. The m6A RNA modification is dynamically and reversibly regulated by three enzymes, namely, m6A methyltransferases (“writers”), m6A demethylases (“erasers”), and m6A binding proteins (“readers”), that establish a complex interplay between m6A incorporation, degradation, and recognition [15, 16]. Enzymes mediating m6A effects are defined as m6A regulators or m6A RNA methylation regulators (Fig. 2) [14, 16]. Methyltransferases install m6A, demethylases remove m6A, and m6A-binding proteins recognize and act upon m6A-modified RNA. While writers and erasers determine the distribution and prevalence of m6A, readers mediate m6A-dependent functions [16]. Accumulating evidence has revealed that writers, erasers, and readers are frequently disordered and are involved in cancer pathogenesis by regulating the expression of oncogenes and/or tumor suppressors, promoting cancer proliferation, development, metastasis, and tumorigenesis [10–12, 14, 17, 18]. While previous studies mostly focused on the role of m6A RNA methylation in tumorigenesis, recent studies have explored m6A regulators in cancer genesis. Nevertheless, the functions and mechanisms of m6A regulators are unknown and need to be elucidated in cancer. Since 2015 [19], studies have revealed that m6A regulatory proteins are regulated by epigenetic modifications, such as ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, and lactylation, or via noncoding RNA action, in cancer. In this review, a concise overview of the current understanding of the role of m6A regulators in cancer is provided. Additionally, the roles and mechanisms of epigenetic modifications of m6A regulators in cancer genesis are delineated. This review will enhance the understanding of the epigenetic regulatory mechanisms of m6A regulators. Fig. 1 Timeline diagram depicting essential discoveries in the field of m6A research Fig. 2 m6A regulator proteins and the underlying mechanisms of m6A modification. The m6A modification of mRNA is mainly catalyzed by the core methylase complex METTL3-WTAP-METTL14. RBM15/15B, VIRMA/KIAA1429, and ZC3H13 are newly identified mRNA modification writers; METTL4, and METTL16 are snRNA modification writhers; and METTL5 and ZCCHC4 are rRNA m6A writers. The m6A modification is removed by FTO, ALKBH5, and ALKBH3. Readers that include members of the YTH domain-containing family, the IGF2BP family, the HNRNP family, eIF3, PRRC2A, and FMRP, recognize modification and affect various functions of RNAs m6A regulator proteins: m6A writers, erasers, and readers The m6A writers, erasers, and readers constitute the molecular composition of m6A RNA methylation regulator proteins [14]. These are proteins that insert (writers), remove (erasers), and recognize (readers) m6A on mRNAs or noncoding RNAs. Proteins that mediate the effects of m6A establish a complex interplay between the above three m6A functions [15]. The effects of m6A on mRNA expression are mediated by an expanding list of m6A readers and m6A writer-complex components, as well as potential erasers. The mechanisms and effects of m6A-modifying regulatory proteins on RNA metabolism are summarized in Table 1. Table 1 The function of m6A modifcation regulators (m6A methylation enzymes) in RNA metabolism Types m6A Regulator Full names Cellular localization Function Ref Writers METTL3 Methyltransferase-like 3 Nucleus Catalyzes methylation reaction/Catalyzes m6A modifcation [5, 20, 21] WTAP Wilms tumor 1- associated protein Nucleus Promotes METTL3-METTL14 heterodimer localization into nuclear speckles [22, 23] METTL14 Methyltransferase-like 14 Nucleus Assists METTL3 to recognize the subtract [20, 22] VIRMA (KIAA1429) Vir-like m6A methyltransferase associated Nucleus Recruits the m6A complex to the special RNA site and interacts with polyadenylation cleavage factors CPSF5 and CPSF6 [24, 25] RBM15 RNA binding motif protein 15 Nucleus Directs METTL3-METTL14 heterodimer to specifc RNA sites [24, 26] RBM15B RNA binding motif protein 15B Nucleus Directs METTL3-METTL14 heterodimer to specifc RNA sites METTL16 Methyltransferase-like 16 Nucleus Catalyzes m6 A modifcation; mediate the m6A methylation of U6 snRNA, noncoding RNAs, and precursor mRNAs (premRNAs) [27–29] ZC3H13 Zinc finger CCCH-type containing 13 Nucleus Bridges WTAP to the mRNA-binding factor Nito;Anchors WTAP in the nucleus to enhance m6A modifcation [30, 31] METTL5 Methyltransferase-like 5 Nucleus Induce the m6A methylation of 18 S rRNA [32] ZCCHC4 Zinc finger CCHC-type containing 4 Nucleus An m6A methyltransferase of 28 S rRNA mediating ribosomal RNA methylation [33–35] METTL4 Methyltransferase-like 4 Nucleus Mediates the m6A methylation of U2 snRNA to regulate pre-mRNA splicing [36] Erasers FTO Fat mass and obesity -associated protein Nucleus Acts as m6A demethylase to promote mRNA splicing and translation; removes m6A modification [37] ALKBH5 AlkB homologue 5 Nucleus Removes m6A modifcation to promote mRNA nuclear processing and mRNA export [38] ALKBH3 AlkB homologue 3 Nucleus Remove m6 A modifcation level [39] Readers YTHDF2 YTH N6-methyladenosine RNA binding protein 2 Cytosol Promotes mRNA degradation [40, 41] YTHDF1 YTH N6-methyladenosine RNA binding protein 1 Cytosol Promotes mRNA translation initiation [42] eIF3 Eukaryotic translation initiation factor 3 subunit A Cytosol Promotes mRNA translation [43] HNRNPA2B1 Heterogeneous nuclear ribonucleoprotein A2/B1 Nucleus Promotes primary miRNA processing and mRNA splicing; promotes primary microRNA processing and mediates nuclear accumulation [44] HNRNPC Heterogeneous nuclear ribonucleoprotein C Nucleus Mediates mRNA splicing and maturity Interacts with m6A-modifed mRNA and affects its enrichment and splicing, generating a phenomenon termed the “m6A switch” [45, 46] HNRNPG Heterogeneous nuclear ribonucleoprotein G Nucleus Mediates mRNA splicing and maturity [45, 46] YTHDC1 YTH domain containing 1 Nucleus Promotes mRNA splicing and transcriptional silencing; regulates RNA nuclear export and splicing [47, 48] YTHDF3 YTH N6-methyladenosine RNA binding protein 3 Cytosol Interacts with YTHDF1 to promote mRNA translation or interacts with YTHDF2 to promote mRNA degradation [49, 50] YTHDC2 YTH domain containing 2 Nucleus; cytosol Improves the translation efciency of target mRNA [51] IGF2BP1 Insulin-like growth factor 2 mRNA binding protein 1 Nucleus; cytosol Promotes the stability and translation of mRNA [52] IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2 Nucleus; cytosol Promotes the stability and translation of mRNA [52] IGF2BP3 Insulin-like growth factor 2 mRNA binding protein 3 Nucleus; cytosol Promotes the stability and translation of mRNA [52] FMRP Fragile X mental retardation protein Nucleus; cytosol Promote the nuclear export and stability of m6A-modifed RNAs [53, 54] PRRC2A Proline rich coiled-coil 2 A Cytosol Bind to a consensus GGACU motif in the Olig2 coding sequence to stabilize Olig2 mRNA [46] RBM33 RNA-binding motif protein 33 Nucleus Forms a complex with ALKBH5 and mediates m6 A demethylation of selected transcripts by regulating ALKBH5 substrate accessibility and activity [55] Writers The currently known m6A methyltransferases, or “m6A writers”, include methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), wilms tumor 1-associated protein (WTAP), RNA binding motif protein 15/15B (RBM15/RBM15B), vir-like m6A methyltransferase associated (VIRMA or KIAA1429), zinc finger CCCH-type containing 13 (ZC3H13), methyltransferase-like 16 (METTL16), methyltransferase-like 4 (METTL4), methyltransferase-like 5 (METTL5), and zinc finger CCHC-type containing 4 (ZCCHC4) (Table 1). The m6A, first reported om 1994, is a multicomponent methyltransferase complex [56]. Subsequently, METTL3, an S-adenosyl-methionine-binding protein with methyltransferase activity, was identified [5]. Recent studies have identified additional components of the m6A methyltransferase complex in mammals, namely, METTL14 [22, 57] and WTAP [22, 23], which are known to form a complex with METTL3 and are anchored to the nucleus to catalyze m6A methyltransferases [22, 23]. While METTL3 functions as a key catalytic component of the m6A methyltransferase complex [5], METTL14 is the core subunit of m6A methyltransferase for m6A installation [22] and WTAP is the regulatory subunit of m6A methyltransferase facilitating m6A modification [22, 23]. RBM15/15B is a subunit of the writer complex and facilitates the recruitment of the m6A writer complex to RNA by interacting with METTL3 in a WTAP-dependent manner [26, 58]. VIRMA (originally known as KIAA1429) is a regulatory subunit of m6A methyltransferase that facilitates m6A installation and functions as a WTAP interactor to associate with the METTL3/METTL14/WTAP complex, coordinatively modulating m6A modification [25, 58]. The ablation of VIRMA leads to a substantial loss of m6A in D. melanogaster [59] and mammalian cells [24]. VIRMA recruits the m6A complex to specific RNA sites and interacts with the polyadenylation cleavage factors CPSF5 and CPSF6, resulting in prolonged 3ʹUTR selection [25]. ZC3H13 interacts with WTAP and anchors it in the nucleus to promote m6A modification [31, 58], facilitating m6A addition and stem cell renewal [31]. Deletion of ZC3H13 resulted in the loss of m6A in D. melanogaster [30, 60] and approximately 80% loss of cellular m6A in mammalian cells [30], suggesting that some m6A sites are formed independent of ZC3H13. Similar to WTAP, ZC3H13 is important for the nuclear localization of the writer complex [31] and is assumed to promote RBM15/15B interaction with WTAP to facilitate methylation [30]. METTL16 mediates the insertion of m6A in small nuclear RNA (snRNAs) (e.g., the spliceosome component U6 snRNA) [27, 29]. METTL16 also functions as a methyltransferase and catalyzes m6A addition in U6-like sequences of MAT2A mRNA, the enzyme required for the biosynthesis of S-adenosylmethionine (SAM) [27, 61]. In addition, METTL16 catalyzes the addition of m6A in a small number of noncoding RNAs and mRNAs [29]. ZCCHC4 is a ribosomal RNA (rRNA)-adenosine-methyltransferase responsible for the formation of a single m6A residue in the 28 S ribosomal RNA (rRNA) [32, 62]. The addition of m6A on unique, highly conserved sites in the 18 S rRNA of eukaryotes is mediated by METTL5-TRMT112 complex, in which METTL5 functions as the catalytic subunit and TRMT112 as an allosteric adaptor [32]. METTL4 mediates m6A methylation of U2 snRNAs to regulate pre-mRNA splicing [36, 63]. Erasers The m6A incorporation and removal in mRNA is a dynamic and reversible process, confirmed in 2011 with the discovery of the fat mass and obesity-associated protein (FTO), which is the first m6A demethylase that removes the methyl group to restore the methylated base to the adenine base [37]. FTO displays m6A demethylase activity and demethylates m6A residues in mRNA indicating the reversibility of this modification [37]. Mauer et al. characterized FTO as a m6A demethylase that regulates mRNA stability and suggested that m6A is a dynamic reversible modification, rekindling interest in the biological relevance of m6A [64]. Furthermore, Zheng et al. discovered the second mammalian m6A demethylase, namely, alkB homologue 5 (ALKBH5), that affects mouse spermatogenesis and demonstrated that m6A is a dynamic reversible modification of mRNA [38]. FTO and ALKBH5 facilitate the removal of m6A and potentially affect different subsets of target mRNAs because of their distinct subcellular and tissue distributions [37, 38]. The first evidence of reversible post-transcriptional modification was given when FTO and ALKBH5 removed addition of m6A in mRNA and certain noncoding RNAs transcribed by RNA polymerase II [37, 38]. By definition, ALKBH3 is an eraser responsible for the removal of the m6A modification on the tRNA [39]. Readers m6A can recruit m6A-binding proteins or m6A readers that mediate m6A-dependent functions to regulate the fate of mRNAs [16, 65]. The m6A readers regulate mRNA nuclear export, splicing, degradation, translation, and stability. The first discovered m6A reader family, providing a mechanistic basis for understanding the effects of m6A on mRNA, was the YT521-B homology (YTH) domain family of proteins [66]. The YTH domain family includes YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2. The nuclear m6A readers are YTHDC1, HNRNPC11, HNRNPA2B1, and HNRNPG, whereas m6A readers in the cytosol are YTHDC2, YTHDF1/2/3, and IGF2BP1/2/3. Different readers have different m6A positioning functions [67]. YTHDF2, the first discovered m6A-binding protein, regulates mRNA degradation by mediating the lifetime of target transcripts [41, 66]. Similarly, YTHDF1 promotes translation of m6A-modified mRNAs in the cytosol [42], while YTHDF3 cooperates with YTHDF1 and YTHDF2 to modulate the translation and degradation of m6A-labelled mRNA and inversely regulates their functions [50]. The insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1/2/3) promote mRNA stability and translation [52]. FMRP enhances the nuclear export and stability of m6A-decorated RNAs [53, 54]. Furthermore, YTHDC1 modulates nuclear export and splicing of m6A-modified RNAs [47, 48], while YTHDC2 regulates the translation and abundance of target genes [51]. As a multiprotein complex that recruits small ribosomal subunits to mRNAs, Eukaryotic initiation factor 3 (eIF3) preferentially binds to m6A-decorated mRNA and is involved in mRNA translation [42, 68]. YTHDF1 recruits eIF3 to the 5’ end of the transcripts, resulting in YTHDF1 looping that modulates initiation of translation [42]. The heterogeneous nuclear ribonucleoprotein (HNRNP) proteins include HNRNPA2B1, HNRNPC, and HNRNPG. HNRNPA2B1 [44] and HNRNPC[45] are active splicing regulators that can selectively bind m6A-decorated mRNAs [45, 69, 70]. HNRNPA2B1 recognizes m6A-labelled primary miRNAs (pri-miRNAs) and regulates alternative splicing events [44] and miRNA biogenesis [44, 71]. HNRNPC recognizes m6A-induced changes in secondary mRNA structures [45], and HNRNPG is an RNA-binding protein involved in the splicing of m6A-labelled mRNA[72]. Proline-rich coiled-coil 2 A (PRRC2A) was later identified as a novel m6A reader that binds to a consensus GGACU motif in the Olig2 coding sequence to stabilize Olig2 mRNA [46]. m6A regulator proteins and cancer Previous studies have shown that m6A is associated with numerous human diseases, including cancer. Pioneering studies have provided molecular evidence of the direct regulatory roles of m6A in cancer [73, 74]. The ablation of METTL3 caused apoptosis and reduced the invasiveness of lung adenocarcinoma cells [73], whereas hypoxia-activated m6A demethylase ALKBH5 induces the accumulation of breast cancer stem cells through HIF-dependent and ALKBH5-mediated m6A demethylation of NANOG mRNA [74]. Recent evidence has indicated that m6A regulatory proteins, i.e., writers, erasers, and readers, play a role in various types of human cancers by contributing to malignancy. This includes cancer cell proliferation, self-renewal of cancer stem cells, and resistance to radiotherapy or chemotherapy. Comprehensive reviews for detailed discussions on the role of m6A regulatory proteins in cancer are already available in literature [11, 12, 14, 17, 18, 67, 75–79]. However, the functions and mechanisms of m6A regulators in cancer remain largely unestablished and need future investigations. Epigenetic modification of m6A regulators and tumorigenesis Epigenetics is a reversible and dynamic process that regulates gene expression without altering DNA. There are four major mechanisms of epigenetic regulation: DNA methylation, histone modification, chromatin structure regulation, and noncoding RNA regulation [80, 81]. All mechanisms, except chromatin structure regulation, have been studied extensively [82]. The histone subunit in the nucleosome possesses a characteristic tail containing specific amino acids for covalent posttranslational modifications (PTMs), such as acetylation, methylation, ubiquitylation, phosphorylation, glycosylation, sumoylation, acylation, glycation, hydroxylation, serotonylation, and ADP-ribosylation [83–86]. Recent studies have suggested that m6A regulators in cancer can be modulated by epigenetic modifications, including ubiquitination, SUMOylation, acetylation, lactylation, O-GlcNAcylation, methylation, phosphorylation, ISGylation, and noncoding RNA. Hence, this section focuses on the roles and mechanisms of the epigenetic modification of m6A regulators in cancer genesis. The effects and mechanisms of epigenetic modification of m6A regulatory proteins in tumorigenesis are summarized in Table 2. Table 2 Epigenetic modification of m6A Regulator proteins in tumorigenesis Modification m6A Regulator Cancer Involved mechanism Ref Ubiquitination FTO CRC GSK3β mediated ubiquitination of demethylase FTO to reduce FTO expression. GSK3β suppresses the progression of CRC through FTO-regulated MZF1/c-Myc axis [87] Ubiquitination FTO CRC Downregulated FTO protein levels was correlated with a high recurrence rate and poor prognosis. Hypoxia restrained FTO protein expression through E3 ligase STRAP-meditaed degradation. FTO exerted a tumor suppressive role by inhibiting MTA1 expression in an m6A-dependent manner. Methylated MTA1 transcripts were recognized by IGF2BP2, which then stabilized its mRNA [88] Ubiquitination FTO Bladder cancer USP18 up-regulates FTO protein, which decreased m6A level in PYCR1 thereby stabilizing PYCR1 transcript to promote bladder cancer initiation and progression [89] Ubiquitination ALKBH5 GBM USP36 stabilize and regulate ALKBH5. The depletion of USP36 drastically decreased the in vivo tumor growth and impaired cell proliferation, deteriorated the self-renewal of GSCs and sensitized GSCs to temozolomide (TMZ) treatment [90] Ubiquitination IGF2BP1 HCC FBXO45 promoted IGF2BP1 ubiquitination and subsequent activation, leading to the upregulation of PLK1 expression and liver tumorigenesis [91] Ubiquitination IGF2BP3 GBC TEAD4 transcriptionally activated LncRNA MNX1-AS1 suppresses IGF2BP3 degradation by recruiting USP16. MNX1-AS1/IGF2BP3 axis inhibits the Hippo signaling pathway and subsequently activates TEAD4. MNX1-AS1 facilitates tumorigenesis, progression and metastasis of GBC through a MNX1-AS1/IGF2BP3/Hippo pathway positive feedback loop [92] Ubiquitination IGF2BP3 CRC Upregulated USP11 protected IGF2BP3 from degradation via deubiquitination thereby promoting tumorigenesis in CRC [93] Ubiquitination HNRNPA2B1 Pancreatic cancer Upregulated Linc01232 by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway promoted the migration and invasion of PC cells [94] Ubiquitination KIAA1429 CRC Upregulated USP29 mediated deubiquitination to stabilize the protein levels of KIAA1429, thereby promoting the stability of SOX8 mRNA through m6A modification to facilitate the malignant proliferation [95] Ubiquitination METTL14 Bladder cancer METTL14 overexpression inhibits BCa cell malignancy through USP38. METTL14 stabilizes USP38 mRNA by inducing m6A modification and enhances USP38 mRNA stability in YTHDF2-dependent manner. USP38 mediates the deubiquitination of METTL14 protein [96] Ubiquitination METTL3 Breast cancer PIN1 interacted with METTL3 and prevented its ubiquitin-dependent proteasomal and lysosomal degradation, thereby increasing the m6A modification of TAZ and EGFR mRNA, resulting in their efficient translation, eventually promoting tumorigenesis in breast cancer [97] SUMOylation METTL3 HCC SUMOylation of METTL3 by SUMO1 was increased high metastatic potential and progression via controlling Snail mRNA homeostasis in an m6A methyltransferase activity-dependent manner [98] SUMOylation METTL3 CRC METTL3, circ_0000677, and ABCC1 were upregulated in CRC. SUMOylation of METTL3 facilitates CRC progression by promoting circ_0000677 in an m6A-dependent manner, thereby upregulating ABCC1 expression [99] SUMOylation METTL3 NSCLC SUMOylation of METTL3 by SUMO1 promotes tumorigenesis. SUMOylation of METTL3, which can be reduced by an SUMO1-specific protease SENP1, significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs [100] SUMOylation FTO HCC SIRT1 exerts an oncogenic role by down-regulating FTO through RANBP2-mediated FTO SUMOylation and degradation [101] SUMOylation HNRNPA2B1 Breast cancer PIAS2-mediated SUMOylated HNRNPA2B1 associates with replication protein A1 (RPA1). HNRNPA2B1 expression may function as an independent predictor of good prognosis. HNRNPA2B1 hinders homologous recombination (HR) repair via limiting RPA availability, thus conferring sensitivity to PARP inhibitors [102] SUMOylation HNRNPA2B1 Glioblastoma Hypoxia promotes the transfer of hnRNP A2/B1 to the cytoplasm by upregulating SUMOylation of hnRNP A2/B1 to eliminate miR-204-3p. Exosomal miR-204-3p promoted tube formation of vascular endothelial cells through the ATXN1/STAT3 pathway. The SUMOylation inhibitor TAK-981 can inhibit the exosome-sorting process of miR-204-3p to inhibit tumor growth and angiogenesis [103] SUMOylation IGF2BP2 Glioma SUMOylation of IGF2BP2 by SUMO1 increased IGF2BP2 protein expression through blocking its ubiquitin-proteasome pathway-dependant degradation. Up-regulated IGF2BP2 enhances the stability of OIP5-AS1, thereby increasing the binding of OIP5-AS1 to miR-495-3p, weakening the binding of miR-495-3p to the 3’UTR of HIF1A and MMP14 mRNA, and ultimately promoting the formation of VM in glioma [104] SUMOylation YTHDF2 NSCLC SUMOylation of YTHDF2 increases its binding affinity of m6A-modified mRNAs leading to cancer progression [105] Acetylation RBM15 ccRCC Histone 3 acetylation modification by EP300/CBP upregulated RBM15 and promotes ccRCC progression. RBM15 enhanced the stability of CXCL11 mRNA in an m6A-dependent manner and promote macrophage infiltration and M2 polarization by promoting the secretion of CXCL11 [106] Acetylation METTL3 ESCC Upregulated METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. KAT2A mediated H3K27 acetylation transcriptionly activate METTL3, whereas SIRT2 exerted the opposite effects. Elvitegravir suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation [107] Acetylation METTL3 Breast cancer Acetylation of METTL3 by EP300/CBP disrupts migration and invasion potential of breast cancer cells [108] Acetylation METTL3 HCC METTL3 acetylation mediated reduced N6-Methyladenosine to promotes MTF1 expression and cancer progression [109] Lactylation METTL3 CRC Lactylation of METTL3 by acetyltransferase p300 induce Mettl3 expression through H3K18la. The lactylation METTL3-JAK1-STAT3 regulatory axis potently induces the immunosuppressive functions of tumor-infiltrating myeloid cells to promote tumor immune escape [110] Lactylation YTHDF2 Ocular melanoma Lactylation of YTHDF2 by EP300 at H3K18la. YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma [111] O-GlcNAcylation YTHDF2 HCC O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 promote its protein stability and oncogenic activity by inhibiting its ubiquitination. Mechanistically, YTHDF2 stabilized MCM2 and MCM5 transcripts in an m6A-dependent manner, thus promoting cell cycle progression and HBV-related HCC tumorigenesis. OGT inhibitor OSMI-1 significantly suppressed HCC progression through targeting YTHDF2 O-GlcNAcylation [112] Methylation RBM15 Leukemia RBM15 is methylated by PRMT1, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4), which in turn interferes with the differentiation process, and can contribute to the development of cancers. RBM15 binds to pre-messenger RNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration [19] Phosphorylation METTL3 CRC ERK Interacts and Phosphorylates METTL3 and WTAP. ERK-dependent METTL3 stabilization affects cellular mRNA m6A methylation, which could contribute to tumorigenesis [113] ISGylation hnRNPA2B1 Ovarian cancer ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells [114] CircEZH2 IGF2BP2 CRC circEZH2 works as sponge of miR-133b to upregulate IGF2BP2 and blocks its ubiquitination-dependent degradation, thereby facilitating the proliferation and migration of CRC cells [115] LncRNA LINRIS IGF2BP2 CRC Upregulated LINRIS promote malignancy. Knockdown of LINRIS resulted in a decreased level of IGF2BP2 through ubiquitination of IGF2BP2 and attenuated MYC-mediated glycolysis in CRC cells [116] Hsa_circ_0026134 IGF2BP3 HCC Hsa_circ_0026134 expression promoted TRIM25- and IGF2BP3-mediated proliferation and invasion through sponging miR-127-5p [117] miR503HG HNRNPA2B1 HCC Decreased miR503HG exists in HCC. Enhanced expression of miR503HG inhibit HCC invasion and metastasis.miR503HG interact with HNRNPA2B1 and promoted its degradation via the ubiquitin-proteasome pathway, which reduced the stability of p52 and p65 mRNA, and simultaneously suppressed the NF-κB signaling pathway in HCC cells [118] lncRNA CYTOR HNRNPC OSCC Upregulated lncRNA CYTOR promote both migration and invasion as well as the EMT. lncRNA CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC [119] circNEIL3 IGF2BP3 Glioma Upregulated circNEIL3 stabilizes IGF2BP3 by preventing HECTD4-mediated ubiquitination and promotes tumorigenesis and progression [120] ccRCC, clear cell renal cell carcinoma; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; ESCC, esophageal squamous cell carcinoma; GBC, gallbladder cancer; GBM, glioblastoma; HCC, hepatocellular carcinoma; HNRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; IGF2BP3, insulin-like growing factor 2 mRNA-binding protein 3; ISG15, ubiquitin-like protein interferon-stimulated gene 15; MCM2, minichromosome maintenance protein 2; MTA1, metastasis-associated protein 1; NSCLC, non-small cell lung carcinoma; OSCC, oral squamous cell carcinoma; PIN1, peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; RANBP2, small ubiquitin-related modifiers (SUMOs) E3 ligase; PRMT1, protein arginine methyltransferase 1; STRAP, serine/threonine kinase receptor associated protein;TAZ, transcriptional coactivator with PDZ-binding motif; TEAD4, TEA domain family member 4; USP, ubiquitin specific peptidase Ubiquitination/deubiquitination Ubiquitination, a highly conserved and key protein PTM, plays an important role in controlling substrate degradation of various proteins [121, 122]. The deubiquitinases (DUBs) can reverse ubiquitination by removing ubiquitin chains, resulting in the termination of ubiquitination and preservation of substrate protein expression levels [122]. The interaction between ubiquitination and deubiquitination plays an essential role in controlling all aspects of biological activity, including cancer. Recent studies have shown that ubiquitination/deubiquitination is involved in the regulation of m6A regulatory proteins in cancer (Fig. 3). Fig. 3 Epigenetic modification of m6A regulator proteins by ubiquitination and SUMOylation in cancer. BC, Breast cancer; CRC, colorectal cancer; GBC, gallbladder cancer; GBM, glioblastoma; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung carcinoma; PC, Pancreatic cancer Ubiquitination/deubiquitination of writers USP38 mediates METTL14 protein deubiquitination; therefore, METTL14 overexpression inhibits bladder cancer cell (BCa) malignancy. METTL14 stabilizes USP38 mRNA through m6A modification in a YTHDF2-dependent manner, demonstrating that METTL14 suppresses BCa progression and forms a feedback loop with USP38 [96]. Similarly, USP29 upregulation mediates KIAA1429 deubiquitination, thereby stabilizing SOX8 mRNA and protein levels through m6A modification to facilitate malignant proliferation in colorectal carcinoma (CRC) [95]. In addition, METTL3 expression has been shown to significantly increase with tumor progression and positively correlate with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) expression in breast cancer tissues. PIN1 interacts with and stabilizes METTL3 by preventing its ubiquitin-dependent proteasomal and lysosomal degradation, thereby increasing the m6A modification of transcriptional coactivator with PDZ-binding motif (TAZ) and epidermal growth factor receptor (EGFR) mRNA, resulting in their efficient translation [97]. This suggests that PIN1 regulates METTL3 through ubiquitination in breast cancer [97]. Ubiquitination/deubiquitination of erasers Downregulation of GSK3β inhibits the ubiquitination of FTO, in turn, stabilizing FTO levels. In succession, FTO increases MZF1 expression by mediating the FTO-regulated m6A modification of MZF1 and consequently, promotes c-Myc expression and cell proliferation [87]. The former study suggests that GSK3β acts as a suppressor in CRC. This observation was later confirmed by other studies, wherein FTO was shown to act as a tumor suppressor in CRC by reducing the expression of metastasis-associated protein 1 (MTA1) in an m6A-dependent manner using IGF2BP2 [88]. The hypoxic tumor microenvironment reduces FTO protein expression by increasing serine/threonine kinase receptor-associated protein (STRAP)-mediated ubiquitination and facilitates CRC metastasis [88]. Ubiquitin-specific peptidase 18 (USP18) upregulates FTO levels through post-translational deubiquitination while decreasing m6A levels in PYCR1, thereby stabilizing the PYCR1 transcript and promoting bladder cancer initiation and progression [89]. Collectively, the above findings define the crucial role played by ubiquitination/deubiquitination in the modulation of FTO in cancer and reveal a novel epigenetic modification of FTO. In addition, USP36 deubiquitinates and stabilizes ALKBH5. The depletion of USP36 drastically decreases glioma tumorigenesis, impairs cell proliferation, deteriorates the self-renewal of GSCs, and increases the sensitivity of GSCs to temozolomide (TMZ) [90]. Ubiquitination/deubiquitination of readers The IGF2BP family of m6A regulatory proteins is also modified by ubiquitination or deubiquitination in cancer. The elevation of E3 ubiquitin ligase F-box/SPRY domain-containing protein 1 (FBXO45) promotes hepatocellular carcinoma (HCC) tumorigenesis through IGF2BP1 ubiquitination and activation, resulting in the upregulation of polo-like kinase (PLK1) expression, suggesting possibility of a new therapeutic regimen for HCC that targets the FBXO45/IGF2BP1/PLK1 axis [91]. TEA domain family member 4 (TEAD4)-transcriptionally activated lncRNA MNX1-AS1 suppresses IGF2BP3 degradation by recruiting USP16. The MNX1-AS1/IGF2BP3 axis inhibits the Hippo signaling pathway, thereby activating TEAD4. Consequently, MNX1-AS1 promotes tumorigenesis, progression, and metastasis of gallbladder cancer (GBC) through an MNX1-AS1/IGF2BP3/Hippo pathway positive feedback mechanism [92]. Similarly, USP11 upregulation protects IGF2BP3 from degradation via deubiquitination and promotes CRC tumorigenesis [93]. Another study has shown that upregulated Linc01232 suppresses the ubiquitin-induced degradation of HNRNPA2B1 and activates A-Raf-induced MAPK/ERK, in turn, promoting the metastasis of pancreatic cancer (PC) [94]. SUMOylation SUMOylation is defined as a post-translational protein modification by conjugation of small ubiquitin-like modifier (SUMO) proteins to substrate proteins. As it is a dynamic as well as reversible process, it has been associated with various cellular processes and is a vital mechanism in cellular stress responses [123]. SUMOylation occurs via an enzymatic cascade involving a dimeric SUMO-activating enzyme E1 (SAE1 and SAE2/UBA2), a single E2 (ubiquitin-conjugating enzyme 9, UBC9), and a limited set of E3 ligases [124]. SUMO-specific proteases (SENPs) cooperate with SUMO molecules to regulate the SUMOylation state of substrate proteins by specifically de-SUMOylating them. SUMOylation is aberrantly upregulated in many cancer stages, including tumorigenesis, epithelial-mesenchymal transition (EMT), metastasis, drug resistance, and antitumor immunity [123, 125]. SUMOylation of writers SUMO1-mediated SUMOylation of METTL3 promotes tumor progression by regulating Snail mRNA homeostasis in an m6A methyltransferase activity-dependent manner in HCC (Fig. 3) [98]. The upregulated expression of METTL3, circ_0000677, and ABCC1 has been observed in CRC. SUMO1-mediated METTL3 SUMOylation facilitates CRC progression and drug resistance by stabilizing circ_0000677 in an m6A-dependent manner, thereby upregulating ABCC1 expression [99]. SUMOylation of METTL3 by SUMO1 promotes tumorigenesis in human non-small cell lung carcinoma (NSCLC). SUMOylation of METTL3, usually reversed by SENP1, significantly inhibits its m6A methyltransferase activity, leading to decreased m6A mRNA levels [100]. SUMOylation of erasers A recent study demonstrated that SIRT1 functions as an oncogene by downregulating FTO via RANBP2-mediated FTO SUMOylation and degradation. SIRT1 activates RANBP2, a critical component of the E3 ligase SUMOs and essential for SUMOylation of FTO at the lysine (K-216) site that promotes FTO degradation. As a tumor suppressor in HCC, the guanine nucleotide-binding protein G(o) subunit alpha (GNAO1) is a m6A downstream target of FTO, and SIRT1-mediated ablation of FTO downregulates GNAO1 mRNA expression through increasing m6A modification [101]. This study suggests that SIRT1 destabilizes FTO, steering GNAO1 as an m6A-modified downstream molecule in HCC tumorigenesis. SUMOylation of readers HNRNPA2B1 expression is an independent predictor of good prognosis in patients with breast cancer. SUMOylation of HNRNPA2 mediated by a protein inhibitor of activated STAT 2 (PIAS2) functions as an endogenous inhibitor of replication protein A1 (RPA1). HNRNPA2B1 hinders homologous recombination (HR) repair by limiting RPA availability and increasing sensitivity to PARP inhibitors [102]. A recent study demonstrated that hypoxia upregulates UBC9 expression and increases SUMOylation of hnRNP A2/B1, promoting its nuclear export to eliminate miR-204-3p in glioma. As exosomal miR-204-3p is known to promote tube formation in vascular endothelial cells via the ATXN1/STAT3 pathway, TAK-981, a SUMOylation inhibitor, can inhibit miR-204-3p sorting into exosomes and inhibits tumor growth and angiogenesis. This suggests that TAK-981 could be a potential therapeutic target for gliomas [103]. SUMOylation of IGF2BP2 by SUMO1 increases IGF2BP2 expression by blocking its ubiquitin-proteasome pathway-dependent degradation. This upregulation stabilizes lncRNA OIP5-AS1, which in turn, binds to miR-495-3p and decreases the association of miR-495-3p, hypoxia-inducible factor 1 alpha (HIF1A), and matrix metalloproteinase 14 (MMP14) mRNA, ultimately promoting the formation of vasculogenic mimicry in glioma [104]. SUMOylation of YTHDF2 at the major site, K571, can be increased by hypoxia and reduced by oxidative stress and SUMOylation inhibitors. The binding affinity of SUMOylated YTHDF2 to m6A-labelled mRNA is significantly increased and resultant deregulated gene expression causes cancer progression in NSCLC [105]. The above study uncovered a new regulatory mechanism for YTHDF2 recognition by m6A-RNA, highlighting the important role of YTHDF2 SUMOylation in the post-transcriptional regulation of gene expression in NSCLC progression [105]. Acetylation Protein acylation plays a vital role in key cellular processes involved in physiology and disease, such as enzyme activity, protein stability, subcellular localization, protein-protein interactions, transcriptional activity, and protein-DNA interactions [126]. Histone acetylation was first identified as a mechanism of gene transcription regulation in the early 1960s [127]. After the first finding, acetylation of the non-histone protein, p53, was discovered in the 1980s, followed by identification of multiple non-histone proteins as targets for acylation [126]. A recent study demonstrated that acetylation plays a role in regulating METTL3 localization and tumorigenic progression in breast cancer (Fig. 4) [108]. METTL3 acetylation is a key PTM for determining its cellular translocation. Li et al. demonstrated that METTL3 acetylation by EP300/CBP hinders the migration and invasion potential of breast cancer cells. It is known that physiological stimuli modulate METTL3 nuclear entry. IL-6-induced deacetylation promotes the nuclear shift of METTL3 via the AMPK/SIRT1 axis, whereas ASP/NAM-mediated acetylation decreases its nucleus import [108]. The METTL3-mediated m6A modification of IL-6 mRNA enhances METTL3 deacetylation and nuclear translocation, whereas SIRT1 inhibition counterbalances this deacetylation-mediated nuclear shift of METTL3. Intriguingly, reconstitution of acetylation-mimetic METTL3 mutant resulted in enhanced translation and compromised metastatic potential, revealing an acetylation-mediated regulatory mechanism that determines the subcellular localization of METTL3 [108]. Additionally, lysine acetyltransferase 2 A (KAT2A)-mediated H3K27 acetylation activates METTL3, promoting cancer metastasis by activating early growth response-1 (EGR1)/Snail signaling in a YTHDF3-dependent manner and revealing a susceptibility to METTL3 blockade in esophageal squamous cell carcinoma. The anti-HIV drug elvitegravir inhibited metastasis by directly targeting METTL3 and enhancing stress-inducible phosphoprotein 1 homology and U-box containing protein 1 (STUB1)-mediated proteasomal degradation in esophageal squamous cell carcinoma (ESCC) [107]. METTL3 acetylation mediated reduced N6-Methyladenosine to promote the expression of metal regulatory transcription factor 1(MTF1) and HCC progression [109]. EP300/CBP-mediated histone 3 acetylation upregulates RBM15 and promotes clear cell renal cell carcinoma (ccRCC) progression by stabilizing CXCL11 mRNA in an m6A-dependent manner [106]. Fig. 4 Epigenetic modification of m6A regulator proteins by acetylation, methylation, O-GlcNAcylation, ISGylation, phosphorylation, and lactylation, or noncoding RNA in cancer. ccRCC, clear cell renal cell carcinoma; CRC, colorectal cancer; ESCC, esophageal squamous cell carcinoma; GBC, gallbladder cancer; GBM, glioblastoma; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung carcinoma; OC, ovarian cancer; OM, ocular melanoma; OSCC, oral squamous cell carcinoma Phosphorylation Phosphorylation is an important epigenetic PTM that strongly correlates with the occurrence and development of multiple diseases, including cancer [128]. Sun et al. demonstrated that activated ERK phosphorylates METTL3 and WTAP. This phosphorylation of METTL3 facilitates its interaction with USP5, thereby stabilizing the m6A METTL3-METTL14-WTAP methyltransferase complex by deubiquitination as shown in Fig. 4 [113]. The loss of METTL3/WTAP phosphorylation reduces the degradation of m6A-labelled pluripotent factor transcripts and traps mouse embryonic stem cells (mESC) in a pluripotent state. METTL3 phosphorylation in ERK-activated tumor cells contributes to CRC tumorigenesis, suggesting that a new function of ERK in regulating m6A methylation exists and that the activation of the ERK-METTL3/WTAP axis promotes tumorigenesis [113]. Lactylation Lactylation is a novel PTM that was initially reported by Zhao et al. (2019) as an indicator of lactate levels and glycolysis [129]. Lactylation has intrinsic connections with cell lactate metabolism which is linked to metabolic rewiring and epigenetic remodeling. Therefore, it represents a novel epigenetic code that affects cellular dysfunction and carcinogenesis [130]. Recent studies have identified lactate-derived lactylation of lysine (Kla) residues on histones as an epigenetic modification that directly stimulates gene transcription from chromatin [129]. Increasing experimental evidence suggests that lactylation plays a role in tumorigenesis. A recent study provides insight into the lactylome profile of hepatitis B virus (HBV)-related HCC, demonstrating an important role for non-histone Kla in HCC progression, preferentially affecting metabolic proteins as shown in Fig. 4 [131]. Hypoxia-induced glycolysis promotes lactylation, thereby stabilizing catenin and aggravating the malignant behavior of CRC cells [132]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the progression and metastasis of CRC by regulating EMT and PI3K/AKT signaling and polarization of macrophages. It acts by mediating migration inhibitory factor (MIF), lactate levels, and protein lactylation [133]. In addition, lactate acts as an essential molecule that boosts regulatory T cells (Treg cells) in the tumor microenvironment by lactylating MOESIN at Lys72. This results in enhanced interaction of MOESIN with transforming growth factor β (TGF-β) receptor I and downstream SMAD3 signaling [134]. Another study showed that HIF1α lactylation enhances transcription of hyaluronic acid (HA) binding protein, KIAA1199, to promote angiogenesis and vasculogenic mimicry in prostate cancer [135]. Therefore, the inhibition of lactylation is a therapeutic target for cancer [136]. Novel studies suggest that lactylation regulates m6A regulator proteins in cancer [110, 111]. Lactylation of METTL3 by acetyltransferase p300 induces Mettl3 expression via H3K18la. Lactylation of the METTL3-JAK1-STAT3 regulatory axis induces immunosuppressive functions in tumor-infiltrating myeloid cells in CRC [110]. Additionally, lactylation drives oncogenesis by facilitating YTHDF2 expression in ocular melanomas [111]. Here, lactylation of YTHDF2 was mediated by EP300 at H3K18la. As YTHDF2 recognizes m6A-labelled PER1 and TP53 mRNAs and promotes their degradation, it accelerates tumorigenesis in ocular melanoma [111]. O-GlcNAcylation The attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is an important PTM that links nutrient flux to gene transcription during virus replication and tumorigenesis [137, 138]. O-GlcNAcylation is dynamically regulated by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). Recently, aberrant O-GlcNAcylation is emerging as a common feature of cancer, owing to deregulated cellular nutrient flux [139, 140]. A recent study, for the first time, showed that O-GlcNAcylation plays a role in the regulation of m6A regulatory proteins in HCC. O-GlcNAcylation of YTHDF2 promotes HBV-associated HCC progression in an m6A-dependent manner, as shown in Fig. 4 [112]. OGT-mediated O-GlcNAcylation of YTHDF2 promotes protein stability and oncogenic activity by inhibiting ubiquitination. YTHDF2 stabilizes minichromosome maintenance protein 2 (MCM2) and MCM5 transcripts in an m6A-dependent manner, promoting cell cycle progression and HBV-related HCC tumorigenesis. OSMI-1, an OGT inhibitor, significantly suppresses HCC progression by targeting YTHDF2 O-GlcNAcylation [112]. Collectively, these findings demonstrate a new regulatory mechanism for YTHDF2 through O-GlcNAcylation and highlight the vital role of YTHDF2 O-GlcNAcylation in m6A RNA methylation and HCC progression. Methylation Protein methylation, first discovered in 1959 [141], is a crucial PTM that regulates the functions of both histone and non-histone proteins [142]. Since the discovery of histone methylation in 1964 [143], numerous studies have unveiled the biology behind protein methylation [144]. Protein methylation occurs mainly at the side chains of lysine (Lys) and arginine (Arg) residues [145]. While lysine residues can be mono-, di-, or trimethylated (me1, me2, and me3, respectively) in a SAM-dependent manner [146], arginine residues can be mono- or demethylated at the respective side-chain by protein arginine methyltransferases (PRMTs) with SAM as the methyl donor [145, 147]. Ample evidence exists that shows involvement of dysregulation of protein methylation in the cancer development and progression [148, 149]. A recent study, for the first time, showed that the arginine methylation plays a role in regulating m6A regulatory proteins in leukemia (Fig. 4) [19]. The RNA-binding protein, RBM15, is methylated at residue R578 by PRMT1, leading to its degradation via E3 ligase (CNOT4)-mediated ubiquitylation. RBM15 binds to the pre-messenger RNA intronic regions of RUNX1, GATA1, TAL1, and c-MPL, a mechanism considered important for megakaryopoiesis. Furthermore, PRMT1 regulates alternative RNA splicing by reducing RBM15 protein concentration [19]. ISGylation Ubiquitin, covalently conjugated to other protein substrates, was first discovered in 1975 [150]. This discovery prompted the finding of ubiquitin-like proteins (UBLs) that are structurally and evolutionarily related to ubiquitin [e.g., interferon-stimulated gene 15 (ISG15), small ubiquitin-like modifier (SUMO), and NEDD8] [151]. The first UBL, ISG15, was discovered in 1979 and can mediate ISGylation or ubiquitin-like covalent modification of other proteins [152]. Two studies suggest a role for ISG15 and ISGylation in cancer progression [151, 153]. A recent study showed that ISG15 suppresses the translation of multidrug resistance-associated protein 2 (MRP2/ABCC2) via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin-resistant ovarian cancer cells (Fig. 4) [114]. While ISG15 expression is downregulated in cisplatin-resistant ovarian cancer cells, overexpression of wild-type ISG15 increases cisplatin-sensitivity of ovarian cancer cells through ISGylated hnRNPA2B1 blockage of its recruitment, and consequently, decreases MRP2/ABCC2 translation and expression [114]. Noncoding RNA Noncoding RNA, or ncRNAs, are functional RNA with limited or no protein-coding abilities but are one of the most common epigenetic regulation mechanisms [154, 155]. NcRNAs interact with target molecules and participate in the regulation of disease development, including cancer [156]. Recent evidence indicates a regulatory role for ncRNAs in the control of m6A regulatory proteins in cancer (Fig. 4). It has been shown that upregulated circNEIL3 stabilizes IGF2BP3 by preventing HECTD4-mediated ubiquitination, in turn, promoting tumorigenesis and progression of gliomas [120]. Another study has demonstrated that circEZH2 works as a sponge for miR-133b to upregulate IGF2BP2 and blocks its ubiquitination-dependent degradation, thereby facilitating the proliferation and migration of CRC cells [115]. Hsa_circ_0026134 promotes TRIM25- and IGF2BP3-mediated proliferation and invasion by sponging miR-127-5p [117]. Upregulated lncRNA CYTOR promotes migration, invasion, and EMT. CYTOR inhibits HNRNPC ubiquitination and stabilizes ZEB1 mRNA [119]. Similarly, upregulated LINRIS is demonstrated to promote malignancy. Knockdown of LINRIS decreases IGF2BP2 levels through IGF2BP2 ubiquitination and attenuates MYC-mediated glycolysis in CRC cells [116]. Another study has shown that decreased miR503HG is present in HCC. Enhanced expression of miR503HG significantly inhibits the invasion and metastasis of HCC. miR503HG interacts with HNRNPA2B1 and promotes its degradation via the ubiquitin-proteasome pathway, resulting in decreased stability of p52 and p65 mRNA while suppressing NF-κB signaling in HCC cells [118]. Conclusion and perspectives While previous studies mainly focused on the role of m6A RNA methylation in tumorigenesis, recent studies provide insight into m6A regulators in cancer genesis. Nevertheless, the functions and mechanisms of m6A regulators are not completely understood and need to be elucidated in cancer. Emerging evidence since 2015 has shown that m6A can be regulated by epigenetic modifications in cancers [19]. In this review, we have discussed the roles and mechanisms of the epigenetic modifications of m6A regulators in cancer genesis and highlighted the crucial role of the epigenetic modification of m6A regulators in tumorigenesis, explaining the regulatory interaction between the epigenetic modification of m6A regulators and m6A modification of RNA in cancer pathogenesis. However, the understanding of epigenetic modification of m6A regulators in cancer is still in its infancy. Crosstalk between histone modifications occurs when one or more histone modifications modulate the recognition, addition, or removal of another modification, or synergistically function to repress or promote the gene transcription [157, 158]. There is exists an interplay between m6A RNA methylation and other epigenetic regulators [159]. The listed epigenetic modifications on m6A regulators are complete, however most of these studies maybe have some disadvantages for their focus on one epigenetic modifications mechanism on m6A regulators. Nevertheless, continuous progress in this field is taking place, and whether these epigenetic regulatory mechanisms are specific to other types of cancer remains to be explored. Little is known about the interplay between two different epigenetic modifications on the same m6A regulators. In addition to ubiquitination, SUMOylation, acetylation, methylation, phosphorylation, O-GlcNAcylation, ISGylation, and lactylation or via noncoding RNA action, whether other epigenetic modification including malonylation, succinylation, and glutarylation, et al. are involved in regulating m6A regulatory proteins remains unclear. Thus, additional studies of the roles of other potential epigenetic modification on m6A regulatory proteins are warranted. Growing evidence suggests targeting m6A regulatory proteins maybe work as a novel therapeutic opportunities for immunotherapy or drug resistance in cancer, and m6A regulatory proteins can be feasibly targeted by small-molecules targeting m6A regulators [160]. Revealing epigenetic regulation mechanism of m6A regulatory proteins in cancer will accelerate the development of promising combination therapeutic regimes containing epigenetic agents and targeting m6A regulatory proteins to overcome chemotherapy resistance, and highlights some promising therapeutic avenues that may be used to surmount chemotherapy drug resistance. Whether the epigenetic modification affect multiple m6A regulatory proteins and how these different epigenetic modification corporate with diverse signaling pathways to determine the role of epigenetic modification in cancer. A profound study on the epigenetic modification network of m6A regulatory proteins process requires extensive investigation. We believe that identifying the effects of epigenetic regulation on m6A regulatory proteins will lead to a better understanding of cancer genesis and provide better therapeutic targets. As concluded, studies about epigenetic modification of m6A regulator proteins is an emerging research field in cancer, and bring a new frontier to cancer research. This implies an additional layer of complexity for the interpretation of m6A modification. The role of epigenetic regulation on m6A regulatory proteins in cancer remains an open conundrum for future investigate on. Acknowledgements Not applicable. Author contributions YuW, HP and HW researched data for the article and contributed substantially to discussion of the content. HW, yaW, HP and YuW wrote the article. JW and JC reviewed and/or edited the manuscript before submission. YuW and HW conceived of and designed the study. HW, ZC and JW provided administrative support. All authors analysed and interpreted the data. All authors read and approved the final manuscript. Funding This work was supported in part by the Science Foundation of AMHT (2022YK01), the Science Foundation of CASIC (2020-LCYL-009), the Science Foundation of ASCH (YN202104), and the Hygiene and Health Development Scientific Research Fostering Plan of Haidian District Beijing (HP2021-19-50701). Data Availability All data generated or analyzed during this study are included in this published article. Declarations Ethics approval and consent to participate Not applicable. Consent for publication All of the authors are aware of and agree to the content of the paper and their being listed as a co-author of the paper. Competing interests The authors declare no competing interests. Abbreviations ALKBH3 AlkB homologue 3 ALKBH5 AlkB homologue 5 BC Breast cancer BCa Bladder cancer ccRCC Clear cell renal cell carcinoma CRC Colorectal cancer DUBs Deubiquitinases eIF3 Eukaryotic translation initiation factor 3 subunit A EGFR Epidermal growth factor receptor EMT Epithelial-mesenchymal transition ESCC Esophageal squamous cell carcinoma FMRP Fragile X mental retardation protein FTO Fat mass and obesity-associated protein GBC Gallbladder cancer GBM Glioblastoma HCC Hepatocellular carcinoma HNRNPC Heterogeneous nuclear ribonucleoprotein C HNRNPA2B1 Heterogeneous nuclear ribonucleoprotein A2/B1 HNRNPG Heterogeneous nuclear ribonucleoprotein G HNRNPA2B1 Heterogeneous nuclear ribonucleoprotein A2/B1 IGF2BP1 Insulin-like growth factor 2 mRNA binding protein 1 IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2 IGF2BP3 Insulin-like growth factor 2 mRNA binding protein 3 ISG15 Ubiquitin-like protein interferon-stimulated gene 15 m6A N6-methyladenosine MCM2 Minichromosome maintenance protein 2 MTA1 Metastasis-associated protein 1 METTL3 Methyltransferase-like protein 3 METTL4 Methyltransferase-like 4 METTL14 Methyltransferase-like 14 METTL5 Methyltransferase-like 5 METTL16 Methyltransferase-like 16 NSCLC Non-small cell lung carcinoma OC Ovarian cancer OM Ocular melanoma OSCC Oral squamous cell carcinoma PC Pancreatic cancer PIN1 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 PTM Posttranslational modification RANBP2 RAN-binding protein 2, a small ubiquitin-related modifiers (SUMOs) E3 ligase RBM15 RNA binding motif protein 15 RBM15B RNA binding motif protein 15B PRMT1 Protein arginine methyltransferase 1 PRRC2A Proline rich coiled-coil 2 A STRAP Serine/threonine kinase receptor associated protein TAZ Transcriptional coactivator with PDZ-binding motif TEAD4 TEA domain family member 4 USP Ubiquitin specific peptidase VIRMA (KIAA1429) Vir-like m6A methyltransferase associated WTAP Wilms tumor 1- associated protein YTHDC1 YTH domain containing 1 YTHDF1 YTH N6-methyladenosine RNA binding protein 1 YTHDF2 YTH N6-methyladenosine RNA binding protein 2 YTHDF3 YTH N6-methyladenosine RNA binding protein 3 YTHDC2 YTH domain containing 2 ZC3H13 Zinc finger CCCH-type containing 13 ZCCHC4 Zinc finger CCHC-type containing 4 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Yumin Wang, Yan Wang and Harsh Patel contributed equally to this work. ==== Refs References 1. Machnicka MA Milanowska K Osman Oglou O Purta E Kurkowska M Olchowik A MODOMICS: a database of RNA modification pathways–2013 update Nucleic Acids Res 2013 41 Database issue D262 267 10.1093/nar/gks1007 23118484 2. Desrosiers R Friderici K Rottman F Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells Proc Natl Acad Sci U S A 1974 71 10 3971 5 10.1073/pnas.71.10.3971. 4372599 3. Perry RP Kelley DE Existence of methylated messenger RNA in mouse L cells Cell 1974 1 1 37 42 10.1016/0092-8674(74)90153-6 4. Sommer S Lavi U Darnell JE Jr The absolute frequency of labeled N-6-methyladenosine in HeLa cell messenger RNA decreases with label time J Mol Biol 1978 124 3 487 99 10.1016/0022-2836(78)90183-3 712844 5. Bokar JA Shambaugh ME Polayes D Matera AG Rottman FM Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase RNA 1997 3 11 1233 47 9409616 6. Clancy MJ Shambaugh ME Timpte CS Bokar JA Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene Nucleic Acids Res 2002 30 20 4509 18 10.1093/nar/gkf573 12384598 7. Zhong S Li H Bodi Z Button J Vespa L Herzog M MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor Plant Cell 2008 20 5 1278 88 10.1105/tpc.108.058883 18505803 8. Boulias K Greer EL Biological roles of adenine methylation in RNA Nat Rev Genet 2023 24 3 143 60 10.1038/s41576-022-00534-0 36261710 9. Liu L Li H Hu D Wang Y Shao W Zhong J Insights into N6-methyladenosine and programmed cell death in cancer Mol Cancer 2022 21 1 32 10.1186/s12943-022-01508-w 35090469 10. An Y Duan H The role of m6A RNA methylation in cancer metabolism Mol Cancer 2022 21 1 14 10.1186/s12943-022-01500-4 35022030 11. Liu Z Zou H Dang Q Xu H Liu L Zhang Y Biological and pharmacological roles of m(6)a modifications in cancer drug resistance Mol Cancer 2022 21 1 220 10.1186/s12943-022-01680-z 36517820 12. He L Li H Wu A Peng Y Shu G Yin G Functions of N6-methyladenosine and its role in cancer Mol Cancer 2019 18 1 176 10.1186/s12943-019-1109-9 31801551 13. Li X Ma S Deng Y Yi P Yu J Targeting the RNA m(6)a modification for cancer immunotherapy Mol Cancer 2022 21 1 76 10.1186/s12943-022-01558-0 35296338 14. Deng LJ Deng WQ Fan SR Chen MF Qi M Lyu WY m6A modification: recent advances, anticancer targeted drug discovery and beyond Mol Cancer 2022 21 1 52 10.1186/s12943-022-01510-2 35164788 15. Fu Y Dominissini D Rechavi G He C Gene expression regulation mediated through reversible m6A RNA methylation Nat Rev Genet 2014 15 293 306 10.1038/nrg3724 24662220 16. Zhao BS Roundtree IA He C Post-transcriptional gene regulation by mRNA modifications Nat Rev Mol Cell Biol 2017 18 1 31 42 10.1038/nrm.2016.132 27808276 17. Wang T Kong S Tao M Ju S The potential role of RNA N6-methyladenosine in Cancer progression Mol Cancer 2020 19 1 88 10.1186/s12943-020-01204-7 32398132 18. Zhou Z Lv J Yu H Han J Yang X Feng D Mechanism of RNA modification N6-methyladenosine in human cancer Mol Cancer 2020 19 1 104 10.1186/s12943-020-01216-3 32513173 19. Zhang L, Tran NT, Su H, Wang R, Lu Y, Tang H, Aoyagi S, Guo A, Khodadadi-Jamayran A, Zhou D et al. (2015). Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing. Elife 4. 10.7554/eLife.07938. 20. Wang P, Doxtader KA, Nam Y. Structural basis for Cooperative function of Mettl3 and Mettl14 methyltransferases [J]. Mol Cell 2016;63(2):306–17. 10.1016/j.molcel.2016.05.041. 21. Wang X Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex Nature 2016 534 575 8 10.1038/nature18298. 27281194 22. Liu J Yue Y Han D A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation Nat Chem Biol 2014 10 2 93 5 10.1038/nchembio.1432. 24316715 23. Ping XL, Sun BF, Wang L et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase [J]. Cell Res 2014;24(2):177–89. 10.1038/cr.2014.3. 24. Schwartz S Mumbach MR Jovanovic M Wang T Maciag K Bushkin GG Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites Cell Rep 2014 8 1 284 96 10.1016/j.celrep.2014.05.048 24981863 25. Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m6A mRNA methylation in 3’UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018;410. 10.1038/s41421-018-0019-0. 26. Patil DP Chen CK Pickering BF Chow A Jackson C Guttman M M(6)a RNA methylation promotes XIST-mediated transcriptional repression Nature 2016 537 7620 369 73 10.1038/nature19342 27602518 27. Pendleton KE Chen B Liu K Hunter OV Xie Y Tu BP Conrad NK The U6 snRNA m(6)a methyltransferase METTL16 regulates SAM synthetase Intron Retention Cell 2017 169 824 835e14 10.1016/j.cell.2017.05.003 28525753 28. Satterwhite ER, Mansfield KD. RNA methyltransferase METTL16: targets and function [J]. Wiley Interdiscip Rev RNA 2022;13(2):e1681. 10.1002/wrna.1681. 29. Warda AS Kretschmer J Hackert P Lenz C Urlaub H Höbartner C Sloan KE Bohnsack MT Human METTL16 is a N(6)-methyladenosine (m(6)A) methyltransferase that targets pre-mRNAs and various non-coding RNAs EMBO Rep 2017 18 2004 14 10.15252/embr.201744940 29051200 30. Knuckles P Lence T Haussmann IU Jacob D Kreim N Carl SH Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)a machinery component Wtap/Fl(2)d Genes Dev 2018 32 5–6 415 29 10.1101/gad.309146.117 29535189 31. Wen J Lv R Ma H Shen H He C Wang J Zc3h13 regulates nuclear RNA m(6)a methylation and mouse embryonic stem cell Self-Renewal Mol Cell 2018 69 6 1028 1038e6 10.1016/j.molcel.2018.02.015 29547716 32. van Tran N Ernst F Hawley BR Zorbas C Ulryck N Hackert P Bohnsack KE Bohnsack MT Jaffrey SR Graille M The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112 Nucleic Acids Res 2019 47 7719 33 10.1093/nar/gkz619 31328227 33. Ma H Wang X Cai J Dai Q Natchiar SK Lv R Chen K Lu Z Chen H Shi YG N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation Nat Chem Biol 2019 15 88 94 10.1038/s41589-018-0184-3 30531910 34. Pinto R Vågbø CB Jakobsson ME Kim Y Baltissen MP O’Donohue MF Guzmán UH Małecki JM Wu J Kirpekar F The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA Nucleic Acids Res 2020 48 830 46 10.1093/nar/gkz1147 31799605 35. Ren W Lu J Huang M Gao L Li D Wang GG Song J Structure and regulation of ZCCHC4 in m(6)A-methylation of 28S rRNA Nat Commun 2019 10 5042 10.1038/s41467-019-12923-x 31695039 36. Chen H Gu L Orellana EA Wang Y Guo J Liu Q Wang L Shen Z Wu H Gregory RI Xing Y Shi Y METTL4 is an snRNA m(6)am methyltransferase that regulates RNA splicing Cell Res 2020 30 544 7 10.1038/s41422-019-0270-4 31913360 37. Jia G Fu Y Zhao X N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO Nat Chem Biol 2011 7 12 885 7 10.1038/nchembio.687 22002720 38. Zheng G Dahl JA Niu Y ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility Mol Cell 2013 49 1 18 29 10.1016/j.molcel.2012.10.015 23177736 39. Ueda Y Ooshio I Fusamae Y Kitae K Kawaguchi M Jingushi K Hase H Harada K Hirata K Tsujikawa K AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells Sci Rep 2017 7 42271 10.1038/srep42271 28205560 40. Du H, Zhao Y, He J et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex [J]. Nat Commun 2016;7:12626. 10.1038/ncomms12626. 41. Wang X Lu Z Gomez A Hon GC Yue Y Han D Fu Y Parisien M Dai Q Jia G N6-methyladenosine-dependent regulation of messenger RNA stability Nature 2014 505 117 20 10.1038/nature12730 24284625 42. Wang X Zhao BS Roundtree IA Lu Z Han D Ma H Weng X Chen K Shi H He C N(6)-methyladenosine modulates Messenger RNA translation efficiency Cell 2015 161 1388 99 10.1016/j.cell.2015.05.014 26046440 43. Meyer KD Patil DP Zhou J Zinoviev A Skabkin MA Elemento O Pestova TV Qian SB Jaffrey SR 5’ UTR m(6)a promotes Cap-Independent translation Cell 2015 163 999 1010 10.1016/j.cell.2015.10.012 26593424 44. Alarcón CR Goodarzi H Lee H Liu X Tavazoie S Tavazoie SF HNRNPA2B1 is a mediator of m(6)A-Dependent Nuclear RNA Processing events Cell 2015 162 1299 308 10.1016/j.cell.2015.08.011 26321680 45. Liu N Dai Q Zheng G He C Parisien M Pan T N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions Nature 2015 518 560 4 10.1038/nature14234 25719671 46. Wu R Li A Sun B Sun JG Zhang J Zhang T Chen Y Xiao Y Gao Y Zhang Q A novel m(6)a reader Prrc2a controls oligodendroglial specification and myelination Cell Res 2019 29 23 41 10.1038/s41422-018-0113-8 30514900 47. Roundtree IA, Luo GZ, Zhang Z, Wang X, Zhou T, Cui Y, Sha J, Huang X, Guerrero L, Xie P, He E, Shen B, He C. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife 2017;6:e31311. 10.7554/eLife.31311. 48. Xiao W Adhikari S Dahal U Chen YS Hao YJ Sun BF Sun HY Li A Ping XL Lai WY Wang X Ma HL Huang CM Yang Y Huang N Jiang GB Wang HL Zhou Q Wang XJ Zhao YL Yang YG Nuclear m(6)a reader YTHDC1 regulates mRNA splicing Mol Cell 2016 61 507 19 10.1016/j.molcel.2016.01.012 26876937 49. Li A, Chen YS, Ping XL et al. Cytoplasmic m(6)a reader YTHDF3 promotes mRNA translation [J]. Cell Res 2017;27(3):444–7. 10.1038/cr.2017.10. 50. Shi H Wang X Lu Z Zhao BS Ma H Hsu PJ Liu C He C YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA Cell Res 2017 27 315 28 10.1038/cr.2017.15 28106072 51. Hsu PJ Zhu Y Ma H Guo Y Shi X Liu Y Qi M Lu Z Shi H Wang J Cheng Y Luo G Dai Q Liu M Guo X Sha J Shen B He C Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis Cell Res 2017 27 1115 27 10.1038/cr.2017.99 28809393 52. Huang H Weng H Sun W Qin X Shi H Wu H Zhao BS Mesquita A Liu C Yuan CL Hu YC Hüttelmaier S Skibbe JR Su R Deng X Dong L Sun M Li C Nachtergaele S Wang Y Hu C Ferchen K Greis KD Jiang X Wei M Qu L Guan JL He C Yang J Chen J Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation Nat Cell Biol 2018 20 285 95 10.1038/s41556-018-0045-z 29476152 53. Edens BM, Vissers C, Su J, Arumugam S, Xu Z, Shi H, Miller N, Ringeling R, Ming F, He GL, Song C, Ma H. Y.C.FMRP modulates neural differentiation through m(6)A-Dependent mRNA Nuclear Export. Cell Rep. 2019;28:845–854e5. 10.1016/j.celrep.2019.06.072. 54. Zhang F Kang Y Wang M Li Y Xu T Yang W Song H Wu H Shu Q Jin P Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets Hum Mol Genet 2018 27 3936 50 30107516 55. Yu F, Zhu AC, Liu S, Gao B, Wang Y, Khudaverdyan N et al. RBM33 is a unique m(6)a RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity. Mol Cell. 2023;83(12):2003-2019. 10.1016/j.molcel.2023.05.010. 56. Bokar JA Rath-Shambaugh ME Ludwiczak R Narayan P Rottman F Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex J Biol Chem 1994 269 26 17697 704 10.1016/S0021-9258(17)32497-3 8021282 57. Wang Y Li Y Toth JI Petroski MD Zhang Z Zhao JC N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells Nat Cell Biol 2014 16 2 191 8 10.1038/ncb2902 24394384 58. Horiuchi K Kawamura T Iwanari H Ohashi R Naito M Kodama T Identification of Wilms’ tumor 1-associating protein complex and its role in alternative splicing and the cell cycle J Biol Chem 2013 288 46 33292 302 10.1074/jbc.M113.500397 24100041 59. Lence T Akhtar J Bayer M Schmid K Spindler L Ho CH M(6)a modulates neuronal functions and sex determination in Drosophila Nature 2016 540 7632 242 7 10.1038/nature20568 27919077 60. Guo J, Tang HW, Li J, Perrimon N, Yan D. (2018). Xio is a component of the Drosophila sex determination pathway and RNA N(6)-methyladenosine methyltransferase complex. Proc. Natl. Acad. Sci. U.S.A. 115(14):3674–3679. 10.1073/pnas.1720945115. 61. Shima H Matsumoto M Ishigami Y Ebina M Muto A Sato Y Kumagai S Ochiai K Suzuki T Igarashi K S-Adenosylmethionine synthesis is regulated by selective N(6)-Adenosine methylation and mRNA degradation involving METTL16 and YTHDC1 Cell Rep 2017 21 3354 63 10.1016/j.celrep.2017.11.092 29262316 62. Sepich-Poore C Zheng Z Schmitt E Wen K Zhang ZS Cui XL Dai Q Zhu AC Zhang L Sanchez Castillo A The METTL5-TRMT112 N(6)-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation J Biol Chem 2022 298 101590 10.1016/j.jbc.2022.101590 35033535 63. Goh YT Koh C Sim DY Roca X Goh W METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing Nucleic Acids Res 2020 48 9250 61 10.1093/nar/gkaa684 32813009 64. Mauer J Luo X Blanjoie A Reversible methylation of m6Am in the 5’ cap controls mRNA stability Nature 2017 541 7637 371 5 10.1038/nature21022 28002401 65. Zaccara S Ries RJ Jaffrey SR Reading, writing and erasing mRNA methylation Nat Rev Mol Cell Biol 2019 20 608 24 10.1038/s41580-019-0168-5 31520073 66. Dominissini D Moshitch-Moshkovitz S Schwartz S Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq Nature 2012 485 7397 201 6 10.1038/nature11112 22575960 67. Jiang X Liu B Nie Z Duan L Xiong Q Jin Z Yang C Chen Y The role of m6A modification in the biological functions and diseases Signal Transduct Target Ther 2021 6 74 10.1038/s41392-020-00450-x 33611339 68. Choe J Lin S Zhang W Liu Q Wang L Ramirez-Moya J Du P Kim W Tang S Sliz P mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis Nature 2018 561 556 60 10.1038/s41586-018-0538-8 30232453 69. David CJ Chen M Assanah M Canoll P Manley JL HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer Nature 2010 463 364 8 10.1038/nature08697 20010808 70. König J Zarnack K Rot G Curk T Kayikci M Zupan B Turner DJ Luscombe NM Ule J iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution Nat Struct Mol Biol 2010 17 909 15 10.1038/nsmb.1838 20601959 71. Alarcón CR Lee H Goodarzi H Halberg N Tavazoie SF N6-methyladenosine marks primary microRNAs for processing Nature 2015 519 482 5 10.1038/nature14281 25799998 72. Liu N Zhou KI Parisien M Dai Q Diatchenko L Pan T N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein Nucleic Acids Res 2017 45 6051 63 10.1093/nar/gkx141 28334903 73. Lin S Choe J Du P Triboulet R Gregory RI The m(6)a methyltransferase METTL3 promotes translation in Human Cancer cells Mol Cell 2016 62 335 45 10.1016/j.molcel.2016.03.021 27117702 74. Zhang C Samanta D Lu H Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA Proc Natl Acad Sci U S A 2016 113 14 E2047 56 10.1073/pnas.1602883113 27001847 75. Kumar S, Nagpal R, Kumar A, Ashraf MU, Bae YS. Immunotherapeutic potential of m6A-Modifiers and MicroRNAs in Controlling Acute myeloid leukaemia. Biomedicines. 2021;9(6):690. 10.3390/biomedicines9060690. 76. Kumar S, Sarthi P, Mani I et al. Epitranscriptomic Approach: to improve the efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH. Cells. 2021;10(9):2250. 10.3390/cells10092250. 77. Liu Y, Yang D, Liu T, Chen J, Yu J, Yi P. N6-methyladenosine-mediated gene regulation and therapeutic implications. Trends Mol Med. 2023;29(6):454-467. 10.1016/j.molmed.2023.03.005. 78. Liu Z Gao L Cheng L The roles of N6-methyladenosine and its target regulatory noncoding RNAs in tumors: classification, mechanisms, and potential therapeutic implications Exp Mol Med 2023 55 3 487 501 10.1038/s12276-023-00944-y 36854773 79. Shen LT Che LR He Z Aberrant RNA m(6)a modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities Cell Death Dis 2023 14 4 236 10.1038/s41419-023-05736-w 37015927 80. Cao J Yan Q Cancer Epigenetics Tumor immunity, and Immunotherapy Trends Cancer 2020 6 7 580 92 10.1016/j.trecan.2020.02.003 32610068 81. Cavalli G Heard E Advances in epigenetics link genetics to the environment and disease Nature 2019 571 7766 489 99 10.1038/s41586-019-1411-0 31341302 82. Wang N Ma T Yu B Targeting epigenetic regulators to overcome drug resistance in cancers Signal Transduct Target Ther 2023 8 1 69 10.1038/s41392-023-01341-7 36797239 83. Dai Z Ramesh V Locasale JW The evolving metabolic landscape of chromatin biology and epigenetics Nat Rev Genet 2020 21 12 737 53 10.1038/s41576-020-0270-8 32908249 84. Chan JC Maze I Nothing is yet set in (hi)stone: novel post-translational modifications regulating chromatin function Trends Biochem Sci 2020 45 10 829 44 10.1016/j.tibs.2020.05.009 32498971 85. Li X Egervari G Wang Y Berger SL Lu Z Regulation of chromatin and gene expression by metabolic enzymes and metabolites Nat Rev Mol Cell Biol 2018 19 9 563 78 10.1038/s41580-018-0029-7 29930302 86. Park JW Han JW Targeting epigenetics for cancer therapy Arch Pharm Res 2019 42 2 159 70 10.1007/s12272-019-01126-z 30806885 87. Zhang Z Gao Q Wang S Kinase GSK3β functions as a suppressor in colorectal carcinoma through the FTO-mediated MZF1/c-Myc axis J Cell Mol Med 2021 25 5 2655 65 10.1111/jcmm.16291 33533172 88. Ruan DY Li T Wang YN Meng Q Li Y Yu K FTO downregulation mediated by hypoxia facilitates colorectal cancer metastasis Oncogene 2021 40 33 5168 81 10.1038/s41388-021-01916-0 34218271 89. Song W Yang K Luo J Gao Z Gao Y Dysregulation of USP18/FTO/PYCR1 signaling network promotes bladder cancer development and progression Aging 2021 13 3 3909 25 10.18632/aging.202359 33461172 90. Chang G, Xie GS, Ma L, Li P, Li L, Richard HT. (2022). USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5. Neuro-oncology. 10.1093/neuonc/noac238. 91. Lin XT, Yu HQ, Fang L, Tan Y, Liu ZY, Wu D et al. (2021). Elevated FBXO45 promotes liver tumorigenesis through enhancing IGF2BP1 ubiquitination and subsequent PLK1 upregulation. Elife 10. 10.7554/eLife.70715. 92. Liu S, Li H, Zhu Y, Ma X, Shao Z, Yang Z, et al. LncRNA MNX1-AS1 sustains inactivation of Hippo pathway through a positive feedback loop with USP16/IGF2BP3 axis in gallbladder cancer. Cancer Lett. 2022;547215862. 10.1016/j.canlet.2022.215862. 93. Huang YY Zhang CM Dai YB Lin JG Lin N Huang ZX USP11 facilitates colorectal cancer proliferation and metastasis by regulating IGF2BP3 stability Am J Translational Res 2021 13 2 480 96 94. Meng LD, Shi GD, Ge WL, Huang XM, Chen Q, Yuan H, et al. Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the a-raf-induced MAPK/ERK signaling pathway. Cancer Lett. 2020;494107–120. 10.1016/j.canlet.2020.08.001. 95. Li J Yang J Chen Z Liu L Wang H Deng Q Promotive role of USP29-mediated deubiquitination in malignant proliferation of colorectal cancer cells via the KIAA1429/SOX8 axis Bosn J Basic Med Sci 2022 10.17305/bjbms.2022.7930 35765958 96. Huang J Zhou W Hao C He Q Tu X The feedback loop of METTL14 and USP38 regulates cell migration, invasion and EMT as well as metastasis in bladder cancer PLoS Genet 2022 18 10 e1010366 10.1371/journal.pgen.1010366 36288387 97. Bhattarai PY METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m(6)A-dependent translation Oncogene 2023 42 1010 23 10.1038/s41388-023-02617-6 36755057 98. Xu H Wang H Zhao W Fu S Li Y Ni W SUMO1 modification of methyltransferase-like 3 promotes tumor progression via regulating snail mRNA homeostasis in hepatocellular carcinoma Theranostics 2020 10 13 5671 86 10.7150/thno.42539 32483411 99. Liu Q Huang Q Liu H He FJ Liu JH Zhou YY SUMOylation of methyltransferase-like 3 facilitates colorectal cancer progression by promoting circ_0000677 in an m(6) A-dependent manner J Gastroenterol Hepatol 2022 37 4 700 13 10.1111/jgh.15775 35030640 100. Du Y Hou G Zhang H Dou J He J Guo Y SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function Nucleic Acids Res 2018 46 10 5195 208 10.1093/nar/gky156 29506078 101. Liu X Liu J Xiao W Zeng Q Bo H Zhu Y SIRT1 regulates N(6) -Methyladenosine RNA modification in Hepatocarcinogenesis by Inducing RANBP2-Dependent FTO SUMOylation Hepatology 2020 72 6 2029 50 10.1002/hep.31222 32154934 102. Zhu S Hou J Gao H Hu Q Kloeber JA Huang J SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses Mol Cell 2023 10.1016/j.molcel.2023.01.003 37311462 103. Guo Q Glioblastoma upregulates SUMOylation of hnRNP A2/B1 to eliminate the tumor suppressor miR-204-3p, accelerating angiogenesis under hypoxia Cell Death Dis 2023 14 147 10.1038/s41419-023-05663-w 36810326 104. Li H Wang D Yi B Cai H Wang Y Lou X SUMOylation of IGF2BP2 promotes vasculogenic mimicry of glioma via regulating OIP5-AS1/miR-495-3p axis Int J Biol Sci 2021 17 11 2912 30 10.7150/ijbs.58035 34345216 105. Hou G Zhao X Li L Yang Q Liu X Huang C SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs Nucleic Acids Res 2021 49 5 2859 77 10.1093/nar/gkab065 33577677 106. Zeng X, Chen K, Li L, Tian J, Ruan W, Hu Z, et al. Epigenetic activation of RBM15 promotes clear cell renal cell carcinoma growth, metastasis and macrophage infiltration by regulating the m6A modification of CXCL11. Free Radic. Biol Med. 2022;184135–147. 10.1016/j.freeradbiomed.2022.03.031. 107. Liao L He Y Li SJ Zhang GG Yu W Yang J Anti-HIV drug Elvitegravir suppresses Cancer Metastasis via increased proteasomal degradation of m6A methyltransferase METTL3 Cancer Res 2022 82 13 2444 57 10.1158/0008-5472.CAN-21-4124 35507004 108. Li Y He X Lu X Gong Z Li Q Zhang L METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions Nat Commun 2022 13 1 6350 10.1038/s41467-022-34209-5 36289222 109. Yang Y Cai Q Fu QSheng Wei Dong L Fan Y Wu Z Reduced N6-Methyladenosine mediated by METTL3 Acetylation promotes MTF1 expression and Hepatocellular Carcinoma Cell Growth Chem Biodivers 2022 19 11 e202200333 10.1002/cbdv.202200333 36149370 110. Xiong J, He J, Zhu J et al. Lactylation-driven METTL3-mediated RNA m(6)a modification promotes immunosuppression of tumor-infiltrating myeloid cells [J]. Mol Cell 2022;82(9):1660–1677e10. 10.1016/j.molcel.2022.02.033. 111. Yu J Chai P Xie M Histone lactylation drives oncogenesis by facilitating m(6)a reader protein YTHDF2 expression in ocular melanoma [J] Genome Biol 2021 22 1 85 10.1186/s13059-021-02308-z 33726814 112. Yang Y Yan Y Yin J Tang N Wang K Huang L O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N(6)-methyladenosine-dependent manner Signal Transduct Target Ther 2023 8 1 63 10.1038/s41392-023-01316-8 36765030 113. Tai H Wang X Zhou J Han X Fang T Gong H Protein kinase Cβ activates fat mass and obesity-associated protein by influencing its ubiquitin/proteasome degradation FASEB J 2017 31 10 4396 406 10.1096/fj.201601159RR 28626026 114. Wang JM Liu BQ Zhang Q Hao L Li C Yan J ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells Biochim Biophys Acta Mol Cell Res 2020 1867 4 118647 10.1016/j.bbamcr.2020.118647 31926942 115. Yao B Zhang Q Yang Z An F Nie H Wang H CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m(6)A-modified CREB1 mRNA Mol Cancer 2022 21 1 140 10.1186/s12943-022-01608-7 35773744 116. Wang Y Lu JH Wu QN Jin Y Wang DS Chen YX LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer Mol Cancer 2019 18 1 174 10.1186/s12943-019-1105-0 31791342 117. Zhang W, Zhu L, Yang G, Zhou B, Wang J, Qu X, et al. Hsa_circ_0026134 expression promoted TRIM25- and IGF2BP3-mediated hepatocellular carcinoma cell proliferation and invasion via sponging miR-127-5p. Biosci Rep. 2020;40(7). 10.1042/BSR20191418. 118. Wang H Liang L Dong Q Huan L He J Li B Long noncoding RNA miR503HG, a prognostic indicator, inhibits tumor metastasis by regulating the HNRNPA2B1/NF-κB pathway in hepatocellular carcinoma Theranostics 2018 8 10 2814 29 10.7150/thno.23012 29774077 119. Zhu W Wang J Liu X Xu Y Zhai R Zhang J lncRNA CYTOR promotes aberrant glycolysis and mitochondrial respiration via HNRNPC-mediated ZEB1 stabilization in oral squamous cell carcinoma Cell Death Dis 2022 13 8 703 10.1038/s41419-022-05157-1 35963855 120. Pan Z Zhao R Li B Qi Y Qiu W Guo Q EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3 Mol Cancer 2022 21 1 16 10.1186/s12943-021-01485-6 35031058 121. Cockram PE Kist M Prakash S Chen SH Wertz IE Vucic D Ubiquitination in the regulation of inflammatory cell death and cancer Cell Death Differ 2021 28 591 605 10.1038/s41418-020-00708-5 33432113 122. Liu J Cheng Y Zheng M Yuan B Wang Z Li X Yin J Ye M Song Y Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways Signal Transduct Target Ther 2021 6 28 10.1038/s41392-020-00418-x 33479196 123. Seeler JS Dejean A SUMO and the robustness of cancer Nat Rev Cancer 2017 17 184 97 10.1038/nrc.2016.143 28134258 124. Kroonen JS Vertegaal A Targeting SUMO signaling to Wrestle Cancer Trends Cancer 2021 7 496 510 10.1016/j.trecan.2020.11.009 33353838 125. Du L Liu W Rosen ST Targeting SUMOylation in cancer Curr Opin Oncol 2021 33 520 5 10.1097/CCO.0000000000000765 34280172 126. Shang S Liu J Hua F Protein acylation: mechanisms, biological functions and therapeutic targets Signal Transduct Target Ther 2022 7 396 10.1038/s41392-022-01245-y 36577755 127. Phillips DM The presence of acetyl groups of histones Biochem J 1963 87 258 63 10.1042/bj0870258 13943142 128. Pang K et al. Role of protein phosphorylation in cell signaling, disease, and the intervention therapy. MedComm. 2022;3(4):e175. 10.1002/mco2.175. 129. Zhang D Tang Z Huang H Zhou G Cui C Weng Y Liu W Kim S Lee S Perez-Neut M Metabolic regulation of gene expression by histone lactylation Nature 2019 574 575 80 10.1038/s41586-019-1678-1 31645732 130. Li X Yang Y Zhang B Lin X Fu X An Y Zou Y Wang JX Wang Z Yu T Lactate metabolism in human health and disease Signal Transduct Target Ther 2022 7 305 10.1038/s41392-022-01151-3 36050306 131. Yang Z Yan C Ma J Peng P Ren X Cai S Shen X Wu Y Zhang S Wang X Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma Nat Metab 2023 5 61 79 10.1038/s42255-022-00710-w 36593272 132. Miao Z Zhao X Liu X Hypoxia induced β-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway Exp Cell Res 2023 422 113439 10.1016/j.yexcr.2022.113439 36464122 133. Wang L Li S Luo H Lu Q Yu S PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages J Exp Clin Cancer Res 2022 41 303 10.1186/s13046-022-02477-0 36242053 134. Gu J Zhou J Chen Q Xu X Gao J Li X Shao Q Zhou B Zhou H Wei S Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells Cell Rep 2022 39 110986 10.1016/j.celrep.2022.110986 35732125 135. Luo Y Yang Z Yu Y Zhang P HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer Int J Biol Macromol 2022 222 2225 43 10.1016/j.ijbiomac.2022.10.014 36209908 136. Pan L Feng F Wu J Fan S Han J Wang S Yang L Liu W Wang C Xu K Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells Pharmacol Res 2022 181 106270 10.1016/j.phrs.2022.106270 35605812 137. Fehl C Hanover JA Tools, tactics and objectives to interrogate cellular roles of O-GlcNAc in disease Nat Chem Biol 2022 18 8 17 10.1038/s41589-021-00903-6 34934185 138. Yang X Qian K Protein O-GlcNAcylation: emerging mechanisms and functions Nat Rev Mol Cell Biol 2017 18 452 65 10.1038/nrm.2017.22 28488703 139. Ferreira JA Peixoto A Neves M Gaiteiro C Reis CA Assaraf YG Santos LL Mechanisms of cisplatin resistance and targeting of cancer stem cells: adding glycosylation to the equation Drug Resist Updat 2016 24 34 54 10.1016/j.drup.2015.11.003 26830314 140. Slawson C Hart GW O-GlcNAc signalling: implications for cancer cell biology Nat Rev Cancer 2011 11 678 84 10.1038/nrc3114 21850036 141. Ambler RP Rees MW Epsilon-N-Methyl-lysine in bacterial flagellar protein Nature 1959 184 56 7 10.1038/184056b0 13793118 142. Bhat KP Ümit Kaniskan H Jin J Gozani O Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease Nat Rev Drug Discov 2021 20 265 86 10.1038/s41573-020-00108-x 33469207 143. Murray K, Epsilon-N-methyl lysine in. Histones Biochem 3:10–5. 10.1021/bi00889a003. 144. Murn J Shi Y The winding path of protein methylation research: milestones and new frontiers Nat Rev Mol Cell Biol 2017 18 517 27 10.1038/nrm.2017.35 28512349 145. Michalak EM Burr ML Bannister AJ Dawson MA The roles of DNA, RNA and histone methylation in ageing and cancer Nat Rev Mol Cell Biol 2019 20 573 89 10.1038/s41580-019-0143-1 31270442 146. Smith BC Denu JM Chemical mechanisms of histone lysine and arginine modifications Biochim Biophys Acta 2009 1789 45 57 10.1016/j.bbagrm.2008.06.005 18603028 147. Bedford MT Richard S Arginine methylation an emerging regulator of protein function Mol Cell 2005 18 263 72 10.1016/j.molcel.2005.04.003 15866169 148. Hamamoto R Saloura V Nakamura Y Critical roles of non-histone protein lysine methylation in human tumorigenesis Nat Rev Cancer 2015 15 110 24 10.1038/nrc3884 25614009 149. Rodríguez-Paredes M Lyko F The importance of non-histone protein methylation in cancer therapy Nat Rev Mol Cell Biol 2019 20 569 70 10.1038/s41580-019-0147-x 31270441 150. Goldstein G Scheid M Hammerling U Schlesinger DH Niall HD Boyse EA Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells Proc Natl Acad Sci U S A 1975 72 11 5 10.1073/pnas.72.1.11 1078892 151. Han HG Moon HW Jeon YJ ISG15 in cancer: beyond ubiquitin-like protein Cancer Lett 2018 438 52 62 10.1016/j.canlet.2018.09.007 30213559 152. Farrell PJ Broeze RJ Lengyel P Accumulation of an mRNA and protein in interferon-treated Ehrlich ascites tumour cells Nature 1979 279 523 5 10.1038/279523a0 571963 153. Yuan Y, Qin H, Li H, Shi W, Bao L, Xu S, Yin J, Zheng L. The functional roles of ISG15/ISGylation in Cancer. Molecules. 2023;28. 10.3390/molecules28031337. 154. Lin X Wu Z Hu H Luo ML Song E Non-coding RNAs rewire cancer metabolism networks Semin Cancer Biol 2021 75 116 26 10.1016/j.semcancer.2020.12.019 33421618 155. Yin X et al. LncRNAs and CircRNAs in cancer. MedComm. 2022;3(2):e141. 10.1002/mco2.141. 156. Zhou L Revisiting cancer hallmarks: insights from the interplay between oxidative stress and non-coding RNAs Mol Biomed 2020 1 4 10.1186/s43556-020-00004-1 35006436 157. Suganuma T Workman JL Signals and combinatorial functions of histone modifications Annu Rev Biochem 2011 80 473 99 10.1146/annurev-biochem-061809-175347 21529160 158. Nagarajan S, Johnsen SA. Crosstalk between histone modifications integrates various signaling inputs to Fine-Tune Transcriptional output - ScienceDirect. Chromatin Signal Dis. 2016:217–39. 10.1016/B978-0-12-802389-1.00012-5. 159. Zhao Y Chen Y Jin M Wang J The crosstalk between m(6)a RNA methylation and other epigenetic regulators: a novel perspective in epigenetic remodeling Theranostics 2021 11 4549 66 10.7150/thno.54967 33754077 160. Zhou X Li C Chen T Li W Wang X Yang Q Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy Mol Cancer 2023 22 1 36 10.1186/s12943-023-01746-6 36810108