
==== Front
Curr Genomics
Curr Genomics
CG
Current Genomics
1389-2029
1875-5488
Bentham Science Publishers

39087001
CG-25-158
10.2174/0113892029296712240405053201
Life Sciences, Genetics & Genomics, Genetics & Heredity
Ramifications of m6A Modification on ncRNAs in Cancer
Mehmood Rashid 1*
1 Department of Life Sciences, College of Science and General Studies, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
* Address correspondence to this author at the Department of Life Sciences, College of Science and General Studies, Alfaisal University, Riyadh, Kingdom of Saudi Arabia; E-mail: rmehmood@alfaisal.edu
09 4 2024
2024
25 3 158170
18 12 2023
12 3 2024
26 3 2024
© 2024 The Author(s). Published by Bentham Science Publishers
2024
The Author(s)
https://creativecommons.org/licenses/by/4.0/ © 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.
N6-methyladenosine (m6A) is an RNA modification wherein the N6-position of adenosine is methylated. It is one of the most prevalent internal modifications of RNA and regulates various aspects of RNA metabolism. M6A is deposited by m6A methyltransferases, removed by m6A demethylases, and recognized by reader proteins, which modulate splicing, export, translation, and stability of the modified mRNA. Recent evidence suggests that various classes of non- coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long con-coding RNAs (lncRNAs), are also targeted by this modification. Depending on the ncRNA species, m6A may affect the processing, stability, or localization of these molecules. The m6A- modified ncRNAs are implicated in a number of diseases, including cancer. In this review, the author summarizes the role of m6A modification in the regulation and functions of ncRNAs in tumor development. Moreover, the potential applications in cancer prognosis and therapeutics are discussed.

Keywords

ncRNAs
m6A modification
cancer
RNA metabolism
long con-coding RNAs
microRNAs
==== Body
pmc1 INTRODUCTION

N6-methyladenosine (m6A) is a common RNA modification that involves the addition of a methyl group to the adenine base of RNA molecules. It is regarded as one of the most prevalent and widely studied RNA modifications in different types of RNA molecules. Initially identified a number of years ago [1], m6A modification has received unprecedented attention recently as it is involved in a number of cellular processes, including mRNA stability, protein translation, RNA conformational changes, modulated protein-RNA interactions, and microRNA processing [2-7]. Widely described as a representative epitranscriptomic modification, m6A has been detected in a range of organisms [8-11]. In humans, it has widespread distribution and dynamics in all major adult and fetal tissues studied so far, accentuating its constitutive impacts [12, 13]. Owing to their critical roles in a number of physiological processes, it is not surprising that anomalies in m6A modification are implicated in a number of pathological conditions, including obesity, developmental defects, neuronal disorders, defective circadian clock, and cancer [14-20]. Our ability to comprehend this modification has significantly enhanced due to the development of a variety of tools that can identify it [21-31]. The last decade has observed great strides in our understanding of how this modification impacts various signaling pathways in various tissues.

Like the epigenetic modifications, m6A modification is reversible and has three groups of proteins that regulate the abundance and impacts of this modification: Writers, Readers and Erasers [32, 33]. The dynamic interplay among the three regulators directs the downstream functions and abundance of m6A. Writers, as the name implies, contribute to the deposition of the methyl group to the target RNA molecules and include a multicomponent methyltransferase complex consisting of Methyltransferase Like 3 (METTL3) [34], METTL14 [35, 36], Wilms Tumor 1 Associated Protein (WTAP) [37, 38], KIAA1429 [39], RNA Binding Motif Protein 15 (RBM15) [40], and zinc finger CCCH domain-containing protein 13 (ZC3H13) [41, 42], wherein METTL3 is the main catalytic component, while METTL14 is required for RNA substrate recognition [43-45]. WTAP is devoid of a catalytic domain and may serve as a platform for interacting with METTL3 and METTL14. Erasers include fat mass and obesity-associated protein (FTO) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) that can actively remove the methyl group [46, 47], making this modification reversible. FTO carries out the oxidation of m6A to A through intermediate products in a stepwise fashion [2]. In addition to its function as a demethylase, FTO regulates alternative splicing of pre-mRNAs, alternative polyA site usage, and 3’UTR processing [48, 49]. ALKBH5 possesses m6A demethylation activity similar to that of FTO but operates in a sequence-specific manner for active demethylation of m6A [47]. Readers of m6A represent a diverse set of molecules that identify and relay the downstream signals with diverse consequences. Our understanding of the downstream effects is still evolving as we identify new molecules that bind the methylated RNA and alter its fate. Thus far, a plethora of proteins have been identified, and the list continues to increase [50]. The biological effects of m6A have been reported to be diverse depending on the molecules that bind this modification. This essentially means that the same m6A modifications may have opposite biological consequences when bound by different readers.

Among the readers, members of highly conserved YTH family proteins bind m6A-containing RNAs with different outcomes for the bound RNA molecules [51]. YTHDC1 binds m6A containing mRNAs in the nucleus and regulates exon inclusion by selectively recruiting or blocking different splicing factors to the binding regions of targeted mRNAs [52]. It also facilitates the nuclear export of m6A-modified mRNAs and promotes XIST-mediated X chromosome silencing [40, 53]. YTHDF family members are primarily cytoplasmic but have different functions, including mRNA stability, localization, and protein translation. YTHDF1, for instance, binds to m6A in the 3’ untranslated region (UTR) and recruits translation initiation machinery to promote translation [7, 54]. YTHDF2 mediates the degradation of m6A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex [55]. The function of YTHDF3 on m6A-modified mRNA depends on its binding partner. When bound to YTHDF1, it regulates mRNA translation [56, 57], and its direct interaction with YTHDF2 leads to m6A-modified mRNA decay [56]. However, recent evidence suggests that YTHDF proteins have redundant functions (195). YTHDC2, the structurally most complex YTH protein by virtue of its domain structure, binds a consensus motif with m6A and can promote translation efficiency while diminishing the mRNA abundance [58-61]. A novel function of RNA m6A in transcriptional regulation via DNA demethylation and chromatin accessibility has also been identified recently (196). Fig. (1) describes the roles of writers, erasers, and readers in m6A modifications and their effects on the downstream pathways.

Most of the functions of m6A modification discussed so far are related to the stability, transport, and processing of mRNA or protein translation. In addition to the above-mentioned functions of m6A on the protein-coding mRNA molecules, various non-coding RNA (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) also serve as targets of m6A modification [62-64]. This m6A modification on lncRNAs has implications for the development of cancers, which is the focus of this review.

The following section discusses the dynamics of m6A modifications in cancer. The deregulation of the associated machinery of m6A modification, including writers, readers, and erasers in various cancers, is summarized. This will be followed by a discussion on the functions of m6A modification on ncRNAs and their effects on cancer progression.

2 m6A DYSREGULATION IN CANCER

m6A modification has been shown to regulate a number of physiological processes, including cell cycle regulation, ageing, and differentiation [65-67]. Various tumor suppressors and oncogenic mRNA molecules are the recipients of m6A modification [67, 68], further substantiating the connection between the modification and cancer. Any alterations in m6A in oncogenes and tumor suppressors may increase or decrease the stability of the target mRNA. For instance, m6A methylation on histidine triad nucleotide-binding protein 2 (HINT2), a tumor suppressor, is recognized by YTHDF1 that promotes its translation and significantly inhibits the progression of ocular melanoma cells in ocular melanoma [68]. Contrarily, mRNA m6A modification on oncogenic CDC25B in the M phase accelerates the translation of CDC25B mRNA through YTHDF1, leading to cell cycle progression and tumorigenicity in cervical cancer [67]. Many other oncogenes, including BCL-2 [69], SOX-2 [70, 71], HBXIP [19], EGFR [72], BRD4 [73], LGR5 [74], c-MYC [75], and MYB [76] are upregulated in an m6A dependent manner leading to tumor progression in multiple cancers. This dual role of targeting both the tumor suppressors and oncogenes, thus regulating both tumour progression and tumour suppression, makes the m6a modification a double-edge sword [77, 78]. Importantly, m6A value has been shown to predict drug response and clinical immunotherapy efficacy [79].

M6A abundance is mediated by the regulating machinery that installs and removes this modification. Additionally, the reading molecules that relay downstream signaling also contribute to the repercussions of the modification. It is not surprising that dysregulation of m6A-related machinery (writers, erasers, and readers) is observed in multiple cancers and has fundamental roles in cancer initiation, progression, metastasis, cancer stemness, drug resistance, and immune evasion [69, 79-81]. Upregulation of METTL3 contributes to the development and progression of prostate cancer by regulating hedgehog pathways [82] and modulating MYC methylation [83]. It also regulates the invasion and metastasis of prostate cancer cells [84]. Additionally, its upregulation is reported in other cancers with concomitant enhanced downstream oncogenic signaling [85-87]. According to multiple published articles, the components of the m6A writer complex are associated with the promotion of cancer [88-92], however, METTL14, and to some extent ZC3H13, are exceptions that act as tumor suppressors in a variety of cancers [93-96] by stabilizing PTEN mRNA and modulating EGFR/PI3K/AKT signaling pathway.

FTO, the eraser of m6A, was initially found to play an oncogenic function in acute myeloid leukemia [97]. Later studies identified its role in tumor progression in liver cancer [98], breast cancer [99], lung cancer [100], colorectal cancer [101], and cervical cancer [102]. However, tumor- suppressing functions of FTO have also been reported [103-105]. ALKBH5 has a context-dependent role and functions both as a tumor suppressor and carcinogen in different cancers and even in the same cancer type [106-111].

The readers of m6A, both nuclear and cytoplasmic, represent a diverse set of molecules with miscellaneous functions, including promoting or hampering the translation of mRNA and accelerating or inhibiting the degradation of mRNA. As these readers relay the downstream signaling, any misregulation will lead to aberrant signaling, resulting in cancer development. YTHDF1/3, for instance, has been shown to promote carcinogenesis [112, 113], while YTHDF2 has both oncogenic and tumor-suppressing functions [114, 115]. IGF2BP1-3 have also been involved with the progression of various cancers [116-118]. Other readers of m6A methylation, including YTHDC1/2, ELAVL1, and hnRNPs, also affect the progression of cancer by regulating a number of important genes implicated in tumorigenesis [119-122]. Anomalies in the expression of m6A regulating molecules have been associated with a poor prognosis, therapy resistance, and impaired antitumour immunity in various cancer types [123, 124].

3 m6A MODIFICATION ON ncRNAs IN CANCER

ncRNAs regulate a number of cellular physiological functions, including regulating target mRNA stability, splicing, processing, and transport, modulating chromatin landscape, DNA repair, and genomic stability. Research in this area continues to uncover new ncRNAs and their roles in various cellular processes, highlighting their significance in biology and medicine.

Like protein-coding mRNAs, ncRNAs also serve as targets for m6A modification. While a large number of ncRNAs are modified by m6A, the functions of this modification in three classes of ncRNAs, i.e., miRNAs, circRNAs, and lncRNAs, are discussed in the following section (Fig. 2).

4 MiRNAs

MiRNAs regulate gene expression post-transcriptionally by base-pairing with target mRNAs affecting their stability or halting translation. Various miRNAs have been reported to be involved in tumorigenesis by acting as oncogenes or tumor suppressors [125]. During their biogenesis, miRNAs are initially transcribed by RNA polymerase II (Pol II) as primary-miRNA (pri-miRNA) with characteristics stem-loop structures. The pri-miRNA are initially processed in the nucleus by Drosha, an RNase III family protein, along with DGCR8 to generate pre-miRNAs which are exported out of the nucleus to the cytoplasm by Exportin-5 (EXP5). In the cytoplasm, Dicer, a member of the RNase III family protein, further processes the pre-miRNAs to generate miRNA duplex. One of the strands of the duplex is selected to carry out its downstream effects in collaboration with Argonaute (AGO) and RISC-loading complex [126]. In addition to the initial transcription by RNA Pol II, the abundance of the mature miRNAs is dependent on the processing machinery. m6A modification on unprocessed pri-miRNA by METTL3 provides an important mark that enhances DGCR8 recognition and the recruitment of processing machinery in the nucleus [5]. Depletion of METTL3 resulted in reduced binding of DGCR8 to pri-miRNAs and, depletion of mature miRNAs and concomitant buildup of unprocessed pri-miRNAs.

M6A modification on miRNAs is identified by readers that may act as inhibitors and accelerators of miRNA processing. Therefore, the abundance of oncogenic or tumor-suppressing miRNAs is linked with the activity of the machinery associated with binding m6A modification. For instance, the NF-κB activator protein NKAP interacts with DGCR8 and promotes the processing of pri-miR-25 through binding to the m6A site on pri-miR-25. M6A deposition is catalyzed by the overexpressed METTL3. Overexpressed mature miR-25 suppresses PHLPP2 which results in the activation of AKT-p70S6K signaling, which eventually leads to pancreatic cancer progression [127, 128]. HNRNPC, a direct binder of the m6A-modified site, recognizes the pri-miR-21 and promotes the expression of miR-21, which targets PDCD4, thus controlling the metastatic potential of glioblastoma [129]. HNRNPA2/B1, on the other hand, is capable of promoting and inhibiting the processing of pri-miRNAs [130]. A number of miRNAs are up or downregulated based on the reader molecules that recognize and bind to m6A modification, thus affecting the production of mature miRNA and, as a result, downstream signaling leading to inhibition or acceleration of cancer development [131-134].

The relationship between m6A and miRNA is two-ways. While m6A modification in pri-miRNA regulates their processing, the mature miRNAs also affect m6A modification by targeting mRNAs of the machinery involved in reading, writing, and erasing m6A. This adds to the complexity of molecular interactions between m6A and miRNAs. miR-33a, which acts as a tumor suppressor in several cancers [134-136], inhibits the proliferation and migration of cancer cells by targeting the 3′-UTR of METTL3, thus reducing the expression of METTL3 [137, 138]. In addition to METTL3, other regulators of m6A dynamics are also targeted by various miRNAs in cancer [139-142].

Adding to the complexity is the fact that miRNAs generally interact with 3’UTR of the target mRNA, a site that is also targeted by m6A methyltransferases [21]. Therefore, the target overlap might affect the ability of miRNAs to exert their effects. This target overlap is predicted to enhance post-transcriptional gene regulation by microRNAs [143, 144]. A model is proposed in which m6A alters the local target mRNA secondary structure to increase the accessibility of Argonaute proteins, resulting in efficient miRNA-mediated regulation [144]. This was practically demonstrated in gastric cancer, wherein a compelling role of m6A was identified in the post-transcriptional regulation of E2F3. m6A-modified motif in E2F3 was required for the interaction between E2F3 3`-UTR and miR-660 [145].

5 circRNAs

circRNAs form a closed loop structure due to covalent bonds between the 3' and 5' ends, leading to a circular or closed structure of these RNA molecules, unlike linear RNAs, which have a start and an end. Initially thought to be mere byproducts of splicing errors, circRNA have emerged as major players in cells where they are abundantly expressed and perform important functions [146, 147]. CircRNAs are implicated in various biological processes employing mechanisms like miRNA sponging, protein interaction, transcriptional regulation, and alternative splicing [148]. M6A modification is important as its deposition at the consensus m6A motifs within circRNAs can efficiently drive their translation initiation, which is driven by initiation factor eIF4G2 and m6A reader YTHDF3 and is augmented by methyltransferase METTL3/14 [149]. An additional function of M6A modification is to mediate circRNAs nucleoplasmic transport. The m6A readers, YTHDC1 and FMRP, are involved in the nuclear and cytoplasmic shuttling of circRNAs [150]. Deposition of m6A modification on circRNAs affect their properties and are reported in various cancers.

Several cirRNAs that are modified by m6A modulate both oncogenic and anti-oncogenic signaling pathways in various cancers. In gastric cancer, METTL14 mediates the m6A level and expression of circORC5 which can sponge miR-30c-2-3p to regulate AKT1S1 and EIF4B, hence promoting cancer progression [151]. M6A modified circDLC1 has been shown to inhibit MMP1-mediated liver cancer progression via interaction with HuR, making it a promising marker for prognosis [152]. CircMETTL3, another circular RNA enriched in m6A fraction can sponge miR-31-5p to upregulate cyclin-dependent kinases (CKD1) expression, thus promoting breast cancer progression [153]. Interestingly, the expression of circMETTL3 is regulated by its host gene, METTL3, in an m6A-dependent fashion. However, METTL3 expression is not dependent on circMETTL3 [153]. Another novel circRNA, circ1662, is highly expressed in in colorectal cancer tissues compared with the paired normal ones, and is correlated with poor prognosis. N6A-induced circ1662 promoted colorectal cancer cell invasion and migration by accelerating YAP1 nuclear transport and regulating the SMAD3 pathway [154]. m6A-modified circRNA, circARHGAP12, is upregulated in the cervical cancer tissue and promotes tumor progression. It promotes oncogenic signaling through m6A-dependent IGF2BP2/FOXM1 pathway [155]. Oncogenic role of METTL3-induced circMYO1C is also reported in PDAC tumorigenesis in an m6A-dependent manner where it enhances PD-L1 mRNA stability [156]. In hepatocellular carcinoma (HCC), CircMAP3K4 highly expressed. M6A modification of circMAP3K4 leads to peptide translation. The translated circMAP3K4-455aa inhibits AIF cleavage and eventually protection of HCC cells from apoptosis [157]. In contrast to these oncogenic roles, circRNAs have been reported to play the role of tumor suppressors as well.

For instance, circDLC1 overexpression inhibited glioma cell proliferation. M6A modification upregulated circDLC1 expression eventually leading to suppression of cellular proliferation [158]. circNDUFB2 inhibits non-small cell lung cancer (NSCLC) progression by degradation of IGF2BPs and activation of anti-tumor immunity [159]. These dual roles of circRNAs makes them exciting molecules for further investigation for their roles in gene regulation and therapeutic targeting [160].

6 LONG NON-CODING RNA (lncRNAs)

The RNA molecules longer than 200 nucleotides in length that do not code for proteins are classified as lncRNAs [161, 162]. While initially thought to be non-functional RNA, research in recent years has revealed that lncRNAs play critical roles in various cellular processes, including gene regulation, epigenetic modifications and cell cycle regulation. Dysregulation of lncRNAs has been implicated in many diseases, including cancer where they have both oncogenic and tumor-suppressive roles [163]. As important players in the complex landscape of cancer biology lncRNAs regulate cancer development and metastasis [164]; therefore, functional modification including m6A will have impact on their roles. Some lncRNAs promote oncogenic signaling by enhancing cell proliferation, blocking cell apoptosis, and facilitating cell invasion and metastasis. Examples include MALAT1, H19, HOTAIR, PVT1 and many others. Interestingly, majority of these lncRNAs undergo m6A modification that has impact on the stemness, cancer progression, metastasis and drug resistance [165-168]. Moreover, the representative lncRNAs with tumor suppressor functions including MEG3, and GAS5 are also targeted by m6A modulators [169-171]. Various lncRNAs collaborate with m6A regulating machinery to regulate a number of downstream molecules implicated in cancer development. For example, KB-1980E6.3 interacts with IGF2BP1 to facilitate m-Myc mRNA stability [172]. Contrarily, FGF13-AS1 prevents Myc mRNA stabilization by binding to IGF2BPs [173]. Similarly, lncRNA GATA3-AS guides KIAA1429 to the 3′ UTR of GATA3 pre-mRNA and facilitates in depositing m6A mark during liver cancer progression (92). Owing to their involvement in regulating important cancer related molecules, various m6A related lncRNAs have been shown to have prognostic potential [174-178].

Although lncRNAs are targeted by m6A regulating machinery and their functions are dependent on m6A methylation, several lncRNAs can also regulate writing, reading and erasing machinery involved in m6A modification. The expression of WTAP, for instance, is regulated by a number of lncRNAs including PCGEM1 in Non-small cell lung cancer [179], LINC00839 in hepatocellular carcinoma [180], SNHG10 in osteosarcoma [181], and DLGAP1-AS1in breast cancer [182]. This mutually reinforcing mechanisms wherein lncRNAs and m6A form a nexus in cancer progression also provide a target for therapeutic interventions.

CONCLUSION

M6A modification in ncRNAs ultimately determines the structure and function of ncRNAs. We appreciate the abundance of this modification due to the development of tools that can detect it. However, despite all these studies, our understanding of modified ncRNAs in cancer is still at its infancy. Many molecular studies are needed to understand the underlying molecular mechanisms that are altered by m6A deposition on ncRNAs during cancer development. M6A modification is one of the many other modifications that RNA molecules are subjected to. How is m6A positioned in an RNA molecule in relation to other modifications needs clarifications.

The connection of m6A modification on ncRNAs and cancer development is established by numerous studies where it is shown to regulates proliferation, differentiation, metastasis, apoptosis and homeostasis. They also have critical roles in prognosis and therapy resistance. Manipulation of m6A modification by using small molecule inhibitors have just been started. A repertoire of molecules targeting writers and erasers of m6A modification have been identified with both natural and synthetic origin, and using AI approaches [183-188].

Preclinical studies highlight the potential of these small-molecule inhibitors of m6A modifiers with oncogenic properties in the treatment of cancer [189-191]. These molecules might have therapeutic potential either alone or in combination with conventional chemotherapy or immunotherapies, and have to be tested in cellular and animal models of cancer development. Although a number of small molecules inhibitors of writers and erasers of m6A have been developed, their non-specificity remains a formidable challenge. The non-specific effects stem from the poor specificity of the inhibitors for the target protein and the ability to modulate m6A levels globally including off target RNAs as well. Thus, the non-specificity of the inhibitors warrant caution in clinical setting. Therefore, new tools have to be established and embedded with the already existing ones. CRISPR-Cas13 is a novel powerful system that can carry out RNA editing and may be employed to regulate and edit differentially expressed and m6A modified ncRNAs to target tumors. Additionally, using larger cohorts of patients in order to identify signatures that might provide predictive and/or prognostic tools will improve our molecular understanding of cancer progression.

ACKNOWLEDGEMENTS

Declared none.

LIST OF ABBREVIATIONS

AGO Argonaute

circRNAs Circular RNAs

EXP5 Exportin-5

HCC Hepatocellular Carcinoma

HINT2 Histidine Triad Nucleotide-binding Protein 2

lncRNAs Long con-coding RNAs

METTL3 Methyltransferase Like 3

miRNAs microRNAs

ncRNAs Non-coding RNAs

NSCLC Non-small Cell Lung Cancer

RBM15 RNA Binding Motif Protein 15

UTR Untranslated Region

WTAP Wilms Tumor 1 Associated Protein

ZC3H13 Zinc Finger CCCH Domain-containing Protein 13

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

Fig. (1) m6A modification and the regulatory proteins. Adenosine of RNA is modified by addition of methyl group “CH3” at the 6th nitrogen atom of adenine by a m6A writer complex. The modification is reversible and the CH3 group is removed by m6A Erasers. The downstream effects (transcriptional and posttranscriptional) of the m6A modification vary depending on the binding proteins, called “Readers”. Various players modulating the metabolism of m6A are shown.

Fig. (2) ncRNAs are also modified by m6A. (A) m6A on microRNAs affects their processing and abundance of mature miRNAs. (B) m6A on circRNAs regulates novel protein synthesis, transport, stability, and cleavage. (C) m6A on lncRNAs regulates their stability, localization, and interaction with other proteins/RNA molecules. M6A modification to all these ncRNAs affect the downstream signaling ultimately regulating carcinogenesis.
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REFERENCES

1 Desrosiers R. Friderici K. Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl. Acad. Sci. 1974 71 10 3971 3975 10.1073/pnas.71.10.3971 4372599
2 Fu Y. Jia G. Pang X. Wang R.N. Wang X. Li C.J. Smemo S. Dai Q. Bailey K.A. Nobrega M.A. Han K.L. Cui Q. He C. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat. Commun. 2013 4 1 1798 10.1038/ncomms2822 23653210
3 Liu N. Dai Q. Zheng G. He C. Parisien M. Pan T. N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions. Nature 2015 518 7540 560 564 10.1038/nature14234 25719671
4 Zhou K.I. Parisien M. Dai Q. Liu N. Diatchenko L. Sachleben J.R. Pan T. N6-methyladenosine modification in a long noncoding rna hairpin predisposes its conformation to protein binding. J. Mol. Biol. 2016 428 5 5 Pt A 822 833 10.1016/j.jmb.2015.08.021 26343757
5 Alarcón C.R. Lee H. Goodarzi H. Halberg N. Tavazoie S.F. N6-methyladenosine marks primary microRNAs for processing. Nature 2015 519 7544 482 485 10.1038/nature14281 25799998
6 Wang X. Lu Z. Gomez A. Hon G.C. Yue Y. Han D. Fu Y. Parisien M. Dai Q. Jia G. Ren B. Pan T. He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 2014 505 7481 117 120 10.1038/nature12730 24284625
7 Wang X. Zhao B.S. Roundtree I.A. Lu Z. Han D. Ma H. Weng X. Chen K. Shi H. He C. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 2015 161 6 1388 1399 10.1016/j.cell.2015.05.014 26046440
8 Leismann J. Spagnuolo M. Pradhan M. Wacheul L. Vu M.A. Musheev M. Mier P. Andrade-Navarro M.A. Graille M. Niehrs C. Lafontaine D.L.J. Roignant J.Y. The 18S ribosomal RNA m 6 A methyltransferase Mettl5 is required for normal walking behavior in Drosophila. EMBO Rep. 2020 21 7 e49443 10.15252/embr.201949443 32350990
9 Tang J. Chen S. Jia G. Detection, regulation, and functions of RNA N6-methyladenosine modification in plants. Plant Commun. 2023 4 3 100546 10.1016/j.xplc.2023.100546 36627844
10 Sendinc E. Valle-Garcia D. Jiao A. Shi Y. Analysis of m6A RNA methylation in Caenorhabditis elegans. Cell Discov. 2020 6 1 47 10.1038/s41421-020-00186-6 32695436
11 Baquero-Perez B. Geers D. Díez J. From A to m6A: The Emerging Viral Epitranscriptome. Viruses 2021 13 6 1049 10.3390/v13061049 34205979
12 Xiao S. Cao S. Huang Q. Xia L. Deng M. Yang M. Jia G. Liu X. Shi J. Wang W. Li Y. Liu S. Zhu H. Tan K. Luo Q. Zhong M. He C. Xia L. The RNA N6-methyladenosine modification landscape of human fetal tissues. Nat. Cell Biol. 2019 21 5 651 661 10.1038/s41556-019-0315-4 31036937
13 Liu J. Li K. Cai J. Zhang M. Zhang X. Xiong X. Meng H. Xu X. Huang Z. Peng J. Fan J. Yi C. Landscape and Regulation of m6A and m6Am Methylome across Human and Mouse Tissues. Mol. Cell 2020 77 2 426 440.e6 10.1016/j.molcel.2019.09.032 31676230
14 Qureshi S.A. Mumtaz A. Shahid S.U. Shabana N.A. rs3751812, a common variant in fat mass and obesity-associated ( FTO ) gene, is associated with serum high and low-density lipoprotein cholesterol in Pakistani individuals. Nutrition 2017 39-40 92 95 10.1016/j.nut.2016.04.008 27324062
15 Ben-Haim M.S. Moshitch-Moshkovitz S. Rechavi G. FTO: linking m6A demethylation to adipogenesis. Cell Res. 2015 25 1 3 4 10.1038/cr.2014.162 25475057
16 Lin Z. Hsu P.J. Xing X. Fang J. Lu Z. Zou Q. Zhang K.J. Zhang X. Zhou Y. Zhang T. Zhang Y. Song W. Jia G. Yang X. He C. Tong M.H. Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis. Cell Res. 2017 27 10 1216 1230 10.1038/cr.2017.117 28914256
17 Richard E.M. Polla D.L. Assir M.Z. Contreras M. Shahzad M. Khan A.A. Razzaq A. Akram J. Tarar M.N. Blanpied T.A. Ahmed Z.M. Abou Jamra R. Wieczorek D. van Bokhoven H. Riazuddin S. Riazuddin S. Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly. Am. J. Hum. Genet. 2019 105 4 869 878 10.1016/j.ajhg.2019.09.007 31564433
18 Yang Y. Han W. Zhang A. Zhao M. Cong W. Jia Y. Wang D. Zhao R. Chronic corticosterone disrupts the circadian rhythm of CRH expression and m6A RNA methylation in the chicken hypothalamus. J. Anim. Sci. Biotechnol. 2022 13 1 29 10.1186/s40104-022-00677-4 35255992
19 Cai X. Wang X. Cao C. Gao Y. Zhang S. Yang Z. Liu Y. Zhang X. Zhang W. Ye L. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018 415 11 19 10.1016/j.canlet.2017.11.018 29174803
20 Liu J. Eckert M.A. Harada B.T. Liu S.M. Lu Z. Yu K. Tienda S.M. Chryplewicz A. Zhu A.C. Yang Y. Huang J.T. Chen S.M. Xu Z.G. Leng X.H. Yu X.C. Cao J. Zhang Z. Liu J. Lengyel E. He C. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat. Cell Biol. 2018 20 9 1074 1083 10.1038/s41556-018-0174-4 30154548
21 Meyer K.D. Saletore Y. Zumbo P. Elemento O. Mason C.E. Jaffrey S.R. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012 149 7 1635 1646 10.1016/j.cell.2012.05.003 22608085
22 Dominissini D. Moshitch-Moshkovitz S. Schwartz S. Salmon-Divon M. Ungar L. Osenberg S. Cesarkas K. Jacob-Hirsch J. Amariglio N. Kupiec M. Sorek R. Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 2012 485 7397 201 206 10.1038/nature11112 22575960
23 Ke S. Alemu E.A. Mertens C. Gantman E.C. Fak J.J. Mele A. Haripal B. Zucker-Scharff I. Moore M.J. Park C.Y. Vågbø C.B. Kusśnierczyk A. Klungland A. Darnell J.E. Jr Darnell R.B. A majority of m 6 A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev. 2015 29 19 2037 2053 10.1101/gad.269415.115 26404942
24 Chen K. Lu Z. Wang X. Fu Y. Luo G.Z. Liu N. Han D. Dominissini D. Dai Q. Pan T. He C. High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. Angew. Chem. Int. Ed. 2015 54 5 1587 1590 10.1002/anie.201410647 25491922
25 Molinie B. Wang J. Lim K.S. Hillebrand R. Lu Z. Van Wittenberghe N. Howard B.D. Daneshvar K. Mullen A.C. Dedon P. Xing Y. Giallourakis C.C. m6A-LAIC-seq reveals the census and complexity of the m6A epitranscriptome. Nat. Methods 2016 13 8 692 698 10.1038/nmeth.3898 27376769
26 Linder B. Grozhik A.V. Olarerin-George A.O. Meydan C. Mason C.E. Jaffrey S.R. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods 2015 12 8 767 772 10.1038/nmeth.3453 26121403
27 Dierks D. Garcia-Campos M.A. Uzonyi A. Safra M. Edelheit S. Rossi A. Sideri T. Varier R.A. Brandis A. Stelzer Y. van Werven F. Scherz-Shouval R. Schwartz S. Multiplexed profiling facilitates robust m6A quantification at site, gene and sample resolution. Nat. Methods 2021 18 9 1060 1067 10.1038/s41592-021-01242-z 34480159
28 Carlile T.M. Rojas-Duran M.F. Zinshteyn B. Shin H. Bartoli K.M. Gilbert W.V. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 2014 515 7525 143 146 10.1038/nature13802 25192136
29 Garcia-Campos M.A. Edelheit S. Toth U. Safra M. Shachar R. Viukov S. Winkler R. Nir R. Lasman L. Brandis A. Hanna J.H. Rossmanith W. Schwartz S. Deciphering the “m6A Code” via Antibody-Independent Quantitative Profiling. Cell 2019 178 3 731 747.e16 10.1016/j.cell.2019.06.013 31257032
30 Zhang Z. Chen L.Q. Zhao Y.L. Yang C.G. Roundtree I.A. Zhang Z. Ren J. Xie W. He C. Luo G.Z. Single-base mapping of m 6 A by an antibody-independent method. Sci. Adv. 2019 5 7 eaax0250 10.1126/sciadv.aax0250 31281898
31 Hendra C. Pratanwanich P.N. Wan Y.K. Goh W.S.S. Thiery A. Göke J. Detection of m6A from direct RNA sequencing using a multiple instance learning framework. Nat. Methods 2022 19 12 1590 1598 10.1038/s41592-022-01666-1 36357692
32 Zaccara S. Ries R.J. Jaffrey S.R. Reading, writing and erasing mRNA methylation. Nat. Rev. Mol. Cell Biol. 2019 20 10 608 624 10.1038/s41580-019-0168-5 31520073
33 Hu Y. Wang S. Liu J. Huang Y. Gong C. Liu J. Xiao Y. Yang S. New sights in cancer: Component and function of N6-methyladenosine modification. Biomed. Pharmacother. 2020 122 109694 10.1016/j.biopha.2019.109694 31918269
34 Bokar J.A. Shambaugh M.E. Polayes D. Matera A.G. Rottman F.M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 1997 3 11 1233 1247 9409616
35 Liu J. Yue Y. Han D. Wang X. Fu Y. Zhang L. Jia G. Yu M. Lu Z. Deng X. Dai Q. Chen W. He C. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 2014 10 2 93 95 10.1038/nchembio.1432 24316715
36 Wang Y. Li Y. Toth J.I. Petroski M.D. Zhang Z. Zhao J.C. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 2014 16 2 191 198 10.1038/ncb2902 24394384
37 Ping X.L. Sun B.F. Wang L. Xiao W. Yang X. Wang W.J. Adhikari S. Shi Y. Lv Y. Chen Y.S. Zhao X. Li A. Yang Y. Dahal U. Lou X.M. Liu X. Huang J. Yuan W.P. Zhu X.F. Cheng T. Zhao Y.L. Wang X. Danielsen J.M.R. Liu F. Yang Y.G. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014 24 2 177 189 10.1038/cr.2014.3 24407421
38 Agarwala S.D. Blitzblau H.G. Hochwagen A. Fink G.R. RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet. 2012 8 6 e1002732 10.1371/journal.pgen.1002732 22685417
39 Schwartz S. Mumbach M.R. Jovanovic M. Wang T. Maciag K. Bushkin G.G. Mertins P. Ter-Ovanesyan D. Habib N. Cacchiarelli D. Sanjana N.E. Freinkman E. Pacold M.E. Satija R. Mikkelsen T.S. Hacohen N. Zhang F. Carr S.A. Lander E.S. Regev A. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 2014 8 1 284 296 10.1016/j.celrep.2014.05.048 24981863
40 Patil D.P. Chen C.K. Pickering B.F. Chow A. Jackson C. Guttman M. Jaffrey S.R. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 2016 537 7620 369 373 10.1038/nature19342 27602518
41 Wen J. Lv R. Ma H. Shen H. He C. Wang J. Jiao F. Liu H. Yang P. Tan L. Lan F. Shi Y.G. He C. Shi Y. Diao J. Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol. Cell 2018 69 6 1028 1038.e6 10.1016/j.molcel.2018.02.015 29547716
42 Knuckles P. Lence T. Haussmann I.U. Jacob D. Kreim N. Carl S.H. Masiello I. Hares T. Villaseñor R. Hess D. Andrade-Navarro M.A. Biggiogera M. Helm M. Soller M. Bühler M. Roignant J.Y. 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 5-6 415 429 10.1101/gad.309146.117 29535189
43 Wang P. Doxtader K.A. Nam Y. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol. Cell 2016 63 2 306 317 10.1016/j.molcel.2016.05.041 27373337
44 Wang X. Feng J. Xue Y. Guan Z. Zhang D. Liu Z. Gong Z. Wang Q. Huang J. Tang C. Zou T. Yin P. Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex. Nature 2016 534 7608 575 578 10.1038/nature18298 27281194
45 Śledź P. Jinek M. Structural insights into the molecular mechanism of the m6A writer complex. eLife 2016 5 e18434 10.7554/eLife.18434 27627798
46 Jia G. Fu Y. Zhao X. Dai Q. Zheng G. Yang Y. Yi C. Lindahl T. Pan T. Yang Y.G. He C. N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011 7 12 885 887 10.1038/nchembio.687 22002720
47 Zheng G. Dahl J.A. Niu Y. Fedorcsak P. Huang C.M. Li C.J. Vågbø C.B. Shi Y. Wang W.L. Song S.H. Lu Z. Bosmans R.P.G. Dai Q. Hao Y.J. Yang X. Zhao W.M. Tong W.M. Wang X.J. Bogdan F. Furu K. Fu Y. Jia G. Zhao X. Liu J. Krokan H.E. Klungland A. Yang Y.G. He C. 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
48 Zhao X. Yang Y. Sun B.F. Shi Y. Yang X. Xiao W. Hao Y.J. Ping X.L. Chen Y.S. Wang W.J. Jin K.X. Wang X. Huang C.M. Fu Y. Ge X.M. Song S.H. Jeong H.S. Yanagisawa H. Niu Y. Jia G.F. Wu W. Tong W.M. Okamoto A. He C. Danielsen J.M.R. Wang X.J. Yang Y.G. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014 24 12 1403 1419 10.1038/cr.2014.151 25412662
49 Bartosovic M. Molares H.C. Gregorova P. Hrossova D. Kudla G. Vanacova S. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing. Nucleic Acids Res. 2017 45 19 11356 11370 10.1093/nar/gkx778 28977517
50 Yang Y. Hsu P.J. Chen Y.S. Yang Y.G. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018 28 6 616 624 10.1038/s41422-018-0040-8 29789545
51 Zhang Z. Theler D. Kaminska K.H. Hiller M. de la Grange P. Pudimat R. Rafalska I. Heinrich B. Bujnicki J.M. Allain F.H.T. Stamm S. The YTH domain is a novel RNA binding domain. J. Biol. Chem. 2010 285 19 14701 14710 10.1074/jbc.M110.104711 20167602
52 Xiao W. Adhikari S. Dahal U. Chen Y.S. Hao Y.J. Sun B.F. Sun H.Y. Li A. Ping X.L. Lai W.Y. Wang X. Ma H.L. Huang C.M. Yang Y. Huang N. Jiang G.B. Wang H.L. Zhou Q. Wang X.J. Zhao Y.L. Yang Y.G. Nuclear m 6 A Reader YTHDC1 Regulates mRNA Splicing. Mol. Cell 2016 61 4 507 519 10.1016/j.molcel.2016.01.012 26876937
53 Roundtree I.A. Luo G.Z. 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 N6-methyladenosine methylated mRNAs. eLife 2017 6 e31311 10.7554/eLife.31311 28984244
54 Wei K. Gao Y. Wang B. Qu Y.X. Methylation recognition protein YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) regulates the proliferation, migration and invasion of osteosarcoma by regulating m6A level of CCR4-NOT transcription complex subunit 7 (CNOT7). Bioengineered 2022 13 3 5236 5250 10.1080/21655979.2022.2037381 35156522
55 Du H. Zhao Y. He J. Zhang Y. Xi H. Liu M. Ma J. Wu L. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nat. Commun. 2016 7 1 12626 10.1038/ncomms12626 27558897
56 Shi H. Wang X. Lu Z. Zhao B.S. Ma H. Hsu P.J. Liu C. He C. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 2017 27 3 315 328 10.1038/cr.2017.15 28106072
57 Li A. Chen Y.S. Ping X.L. Yang X. Xiao W. Yang Y. Sun H.Y. Zhu Q. Baidya P. Wang X. Bhattarai D.P. Zhao Y.L. Sun B.F. Yang Y.G. Cytoplasmic m6A reader YTHDF3 promotes mRNA translation. Cell Res. 2017 27 3 444 447 10.1038/cr.2017.10 28106076
58 Bailey A.S. Batista P.J. Gold R.S. Chen Y.G. de Rooij D.G. Chang H.Y. Fuller M.T. The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. eLife 2017 6 e26116 10.7554/eLife.26116 29087293
59 Hsu P.J. 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 N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017 27 9 1115 1127 10.1038/cr.2017.99 28809393
60 Wojtas M.N. Pandey R.R. Mendel M. Homolka D. Sachidanandam R. Pillai R.S. Regulation of m6A Transcripts by the 3′→5′ RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline. Mol. Cell 2017 68 2 374 387.e12 10.1016/j.molcel.2017.09.021 29033321
61 Tanabe A. Tanikawa K. Tsunetomi M. Takai K. Ikeda H. Konno J. Torigoe T. Maeda H. Kutomi G. Okita K. Mori M. Sahara H. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett. 2016 376 1 34 42 10.1016/j.canlet.2016.02.022 26996300
62 Zhou C. Molinie B. Daneshvar K. Pondick J.V. Wang J. Van Wittenberghe N. Xing Y. Giallourakis C.C. Mullen A.C. Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs. Cell Rep. 2017 20 9 2262 2276 10.1016/j.celrep.2017.08.027 28854373
63 Yang D. Qiao J. Wang G. Lan Y. Li G. Guo X. Xi J. Ye D. Zhu S. Chen W. Jia W. Leng Y. Wan X. Kang J. N 6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucleic Acids Res. 2018 46 8 3906 3920 10.1093/nar/gky130 29529255
64 Yang Z. Li J. Feng G. Gao S. Wang Y. Zhang S. Liu Y. Ye L. Li Y. Zhang X. MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3′-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein. J. Biol. Chem. 2017 292 9 3614 3623 10.1074/jbc.M116.749689 28104805
65 Li L. Sun Y. Davis A.E. Shah S.H. Hamed L.K. Wu M.R. Lin C.H. Ding J.B. Wang S. Mettl14-mediated m6A modification ensures the cell-cycle progression of late-born retinal progenitor cells. Cell Rep. 2023 42 6 112596 10.1016/j.celrep.2023.112596 37269288
66 Luo H. Liu W. Zhang Y. Yang Y. Jiang X. Wu S. Shao L. METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells. Stem Cell Res. Ther. 2021 12 1 159 10.1186/s13287-021-02223-x 33648590
67 Li H. Zhong Y. Cao G. Shi H. Liu Y. Li L. Yin P. Chen J. Xiao Z. Du B. METTL3 promotes cell cycle progression via m 6 A/YTHDF1-dependent regulation of CDC25B translation. Int. J. Biol. Sci. 2022 18 8 3223 3236 10.7150/ijbs.70335 35637959
68 Jia R. Chai P. Wang S. Sun B. Xu Y. Yang Y. Ge S. Jia R. Yang Y.G. Fan X. m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation. Mol. Cancer 2019 18 1 161 10.1186/s12943-019-1088-x 31722709
69 Wang H. Xu B. Shi J. N6-methyladenosine METTL3 promotes the breast cancer progression via targeting Bcl-2. Gene 2020 722 144076 10.1016/j.gene.2019.144076 31454538
70 Visvanathan A. Patil V. Arora A. Hegde A.S. Arivazhagan A. Santosh V. Somasundaram K. Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 2018 37 4 522 533 10.1038/onc.2017.351 28991227
71 Li T. Hu P.S. Zuo Z. Lin J.F. Li X. Wu Q.N. Chen Z.H. Zeng Z.L. Wang F. Zheng J. Chen D. Li B. Kang T.B. Xie D. Lin D. Ju H.Q. Xu R.H. METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol. Cancer 2019 18 1 112 10.1186/s12943-019-1038-7 31230592
72 Lin S. Choe J. Du P. Triboulet R. Gregory R.I. The m 6 A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol. Cell 2016 62 3 335 345 10.1016/j.molcel.2016.03.021 27117702
73 Choe J. Lin S. Zhang W. Liu Q. Wang L. Ramirez-Moya J. Du P. Kim W. Tang S. Sliz P. Santisteban P. George R.E. Richards W.G. Wong K.K. Locker N. Slack F.J. Gregory R.I. mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis. Nature 2018 561 7724 556 560 10.1038/s41586-018-0538-8 30232453
74 Zhang Y. Kang M. Zhang B. Meng F. Song J. Kaneko H. Shimamoto F. Tang B. RETRACTED ARTICLE: m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5. Mol. Cancer 2019 18 1 185 10.1186/s12943-019-1116-x 31849331
75 Vu L.P. Pickering B.F. Cheng Y. Zaccara S. Nguyen D. Minuesa G. Chou T. Chow A. Saletore Y. MacKay M. Schulman J. Famulare C. Patel M. Klimek V.M. Garrett-Bakelman F.E. Melnick A. Carroll M. Mason C.E. Jaffrey S.R. Kharas M.G. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 2017 23 11 1369 1376 10.1038/nm.4416 28920958
76 Weng H. Huang H. Wu H. Qin X. Zhao B.S. Dong L. Shi H. Skibbe J. Shen C. Hu C. Sheng Y. Wang Y. Wunderlich M. Zhang B. Dore L.C. Su R. Deng X. Ferchen K. Li C. Sun M. Lu Z. Jiang X. Marcucci G. Mulloy J.C. Yang J. Qian Z. Wei M. He C. Chen J. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification. Cell Stem Cell 2018 22 2 191 205.e9 10.1016/j.stem.2017.11.016 29290617
77 Wang S. Chai P. Jia R. Jia R. Novel insights on m6A RNA methylation in tumorigenesis: A double-edged sword. Mol. Cancer 2018 17 1 101 10.1186/s12943-018-0847-4 30031372
78 Gao R. Ye M. Liu B. Wei M. Ma D. Dong K. m6A Modification: A Double-Edged Sword in Tumor Development. Front. Oncol. 2021 11 679367 10.3389/fonc.2021.679367 34381710
79 Zou C. He Q. Feng Y. Chen M. Zhang D. A m6Avalue predictive of prostate cancer stemness, tumor immune landscape and immunotherapy response. NAR Cancer 2022 4 1 zcac010 10.1093/narcan/zcac010 35350771
80 Xie J. Ba J. Zhang M. Wan Y. Jin Z. Yao Y. The m6A methyltransferase METTL3 promotes the stemness and malignant progression of breast cancer by mediating m6A modification on SOX2. J. BUON 2021 26 2 444 449 34076991
81 Fang Z. Mei W. Qu C. Lu J. Shang L. Cao F. Li F. Role of m6A writers, erasers and readers in cancer. Exp. Hematol. Oncol. 2022 11 1 45 10.1186/s40164-022-00298-7 35945641
82 Cai J. Yang F. Zhan H. Situ J. Li W. Mao Y. Luo Y. RNA m6A Methyltransferase METTL3 Promotes The Growth Of Prostate Cancer By Regulating Hedgehog Pathway. OncoTargets Ther. 2019 12 9143 9152 10.2147/OTT.S226796 31806999
83 Yuan Y. Du Y. Wang L. Liu X. The M6A methyltransferase METTL3 promotes the development and progression of prostate carcinoma via mediating MYC methylation. J. Cancer 2020 11 12 3588 3595 10.7150/jca.42338 32284755
84 Chen Y. Pan C. Wang X. Xu D. Ma Y. Hu J. Chen P. Xiang Z. Rao Q. Han X. Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells. Theranostics 2021 11 16 7640 7657 10.7150/thno.61178 34335955
85 Chen S.L. Liu L.L. Wang C.H. Lu S.X. Yang X. He Y.F. Zhang C.Z. Yun J.P. Loss of RDM1 enhances hepatocellular carcinoma progression via p53 and Ras/Raf/ERK pathways. Mol. Oncol. 2020 14 2 373 386 10.1002/1878-0261.12593 31670863
86 Chen M. Wei L. Law C.T. Tsang F.H.C. Shen J. Cheng C.L.H. Tsang L.H. Ho D.W.H. Chiu D.K.C. Lee J.M.F. Wong C.C.L. Ng I.O.L. Wong C.M. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology 2018 67 6 2254 2270 10.1002/hep.29683 29171881
87 Gao Q. Zheng J. Ni Z. Sun P. Yang C. Cheng M. Wu M. Zhang X. Yuan L. Zhang Y. Li Y. The m 6 A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells. Stem Cells Int. 2020 2020 1 12 10.1155/2020/8849218 32676121
88 Fan Y. Li X. Sun H. Gao Z. Zhu Z. Yuan K. Role of WTAP in Cancer: From Mechanisms to the Therapeutic Potential. Biomolecules 2022 12 9 1224 10.3390/biom12091224 36139062
89 Kuai Y. Gong X. Ding L. Li F. Lei L. Gong Y. Liu Q. Tan H. Zhang X. Liu D. Ren G. Pan H. Shi Y. Berberich-Siebelt F. Mao Z. Zhou R. Wilms’ tumor 1-associating protein plays an aggressive role in diffuse large B-cell lymphoma and forms a complex with BCL6 via Hsp90. Cell Commun. Signal. 2018 16 1 50 10.1186/s12964-018-0258-6 30143009
90 Yu H. Zhao K. Zeng H. Li Z. Chen K. Zhang Z. Li E. Wu Z. N6-methyladenosine (m6A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability. Biomed. Pharmacother. 2021 133 111075 10.1016/j.biopha.2020.111075 33378974
91 Qian J.Y. Gao J. Sun X. Cao M.D. Shi L. Xia T.S. Zhou W.B. Wang S. Ding Q. Wei J.F. KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene 2019 38 33 6123 6141 10.1038/s41388-019-0861-z 31285549
92 Lan T. Li H. Zhang D. Xu L. Liu H. Hao X. Yan X. Liao H. Chen X. Xie K. Li J. Liao M. Huang J. Yuan K. Zeng Y. Wu H. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol. Cancer 2019 18 1 186 10.1186/s12943-019-1106-z 31856849
93 Gong P.J. Shao Y.C. Yang Y. Song W.J. He X. Zeng Y.F. Huang S.R. Wei L. Zhang J.W. Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer. Front. Oncol. 2020 10 578963 10.3389/fonc.2020.578963 33363011
94 Yang X. Zhang S. He C. Xue P. Zhang L. He Z. Zang L. Feng B. Sun J. Zheng M. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol. Cancer 2020 19 1 46 10.1186/s12943-020-1146-4 32111213
95 Yao Q. He L. Gao X. Tang N. Lin L. Yu X. Wang D. The m6A Methyltransferase METTL14-Mediated N6-Methyladenosine Modification of PTEN mRNA Inhibits Tumor Growth and Metastasis in Stomach Adenocarcinoma. Front. Oncol. 2021 11 699749 10.3389/fonc.2021.699749 34476213
96 Shi Y. Zhuang Y. Zhang J. Chen M. Wu S. METTL14 Inhibits Hepatocellular Carcinoma Metastasis Through Regulating EGFR/PI3K/AKT Signaling Pathway in an m6A-Dependent Manner. Cancer Manag. Res. 2020 12 13173 13184 10.2147/CMAR.S286275 33380825
97 Li Z. Weng H. Su R. Weng X. Zuo Z. Li C. Huang H. Nachtergaele S. Dong L. Hu C. Qin X. Tang L. Wang Y. Hong G.M. Huang H. Wang X. Chen P. Gurbuxani S. Arnovitz S. Li Y. Li S. Strong J. Neilly M.B. Larson R.A. Jiang X. Zhang P. Jin J. He C. Chen J. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase. Cancer Cell 2017 31 1 127 141 10.1016/j.ccell.2016.11.017 28017614
98 Bian X. Shi D. Xing K. Zhou H. Lu L. Yu D. Wu W. AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation. Clin. Transl. Med. 2021 11 3 e352 10.1002/ctm2.352 33783988
99 Niu Y. Lin Z. Wan A. Chen H. Liang H. Sun L. Wang Y. Li X. Xiong X. Wei B. Wu X. Wan G. RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol. Cancer 2019 18 1 46 10.1186/s12943-019-1004-4 30922314
100 Liu J. Ren D. Du Z. Wang H. Zhang H. Jin Y. m 6 A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression. Biochem. Biophys. Res. Commun. 2018 502 4 456 464 10.1016/j.bbrc.2018.05.175 29842885
101 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 2665 10.1111/jcmm.16291 33533172
102 Zou D. Dong L. Li C. Yin Z. Rao S. Zhou Q. The m6A eraser FTO facilitates proliferation and migration of human cervical cancer cells. Cancer Cell Int. 2019 19 1 321 10.1186/s12935-019-1045-1 31827395
103 Zhang C. Chen L. Lou W. Su J. Huang J. Liu A. Xu Y. He H. Gao Y. Xu D. Li Q. Aberrant activation of m6A demethylase FTO renders HIF2α low/− clear cell renal cell carcinoma sensitive to BRD9 inhibitors. Sci. Transl. Med. 2021 13 613 eabf6045 10.1126/scitranslmed.abf6045 34586831
104 Jiao M. Tian R. Liu G. Liu X. Wei Q. Yan J. Wang K. Yang P. Circular RNA and Messenger RNA Expression Profile and Competing Endogenous RNA Network in Subchondral Bone in Osteonecrosis of the Femoral Head. DNA Cell Biol. 2021 40 1 61 69 10.1089/dna.2020.5894 33185492
105 Rong Z.X. Li Z. He J.J. Liu L.Y. Ren X.X. Gao J. Mu Y. Guan Y.D. Duan Y.M. Zhang X.P. Zhang D.X. Li N. Deng Y.Z. Sun L.Q. Downregulation of Fat Mass and Obesity Associated (FTO) Promotes the Progression of Intrahepatic Cholangiocarcinoma. Front. Oncol. 2019 9 369 10.3389/fonc.2019.00369 31143705
106 Nagaki Y. Motoyama S. Yamaguchi T. Hoshizaki M. Sato Y. Sato T. Koizumi Y. Wakita A. Kawakita Y. Imai K. Nanjo H. Watanabe H. Imai Y. Minamiya Y. Kuba K. m 6 A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis. Genes Cells 2020 25 8 547 561 10.1111/gtc.12792 32449584
107 Nie S. Zhang L. Liu J. Wan Y. Jiang Y. Yang J. Sun R. Ma X. Sun G. Meng H. Xu M. Cheng W. ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer. J. Exp. Clin. Cancer Res. 2021 40 1 284 10.1186/s13046-021-02088-1 34496932
108 Zhang X. Wang F. Wang Z. Yang X. Yu H. Si S. Lu J. Zhou Z. Lu Q. Wang Z. Yang H. ALKBH5 promotes the proliferation of renal cell carcinoma by regulating AURKB expression in an m6A-dependent manner. Ann. Transl. Med. 2020 8 10 646 10.21037/atm-20-3079 32566583
109 Qiu X. Yang S. Wang S. Wu J. Zheng B. Wang K. Shen S. Jeong S. Li Z. Zhu Y. Wu T. Wu X. Wu R. Liu W. Wang H.Y. Chen L. M6A Demethylase ALKBH5 Regulates PD-L1 Expression and Tumor Immunoenvironment in Intrahepatic Cholangiocarcinoma. Cancer Res. 2021 81 18 4778 4793 10.1158/0008-5472.CAN-21-0468 34301762
110 Chen Y. Zhao Y. Chen J. Peng C. Zhang Y. Tong R. Cheng Q. Yang B. Feng X. Lu Y. Xie H. Zhou L. Wu J. Zheng S. ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1. Mol. Cancer 2020 19 1 123 10.1186/s12943-020-01239-w 32772918
111 Tang B. Yang Y. Kang M. Wang Y. Wang Y. Bi Y. He S. Shimamoto F. m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol. Cancer 2020 19 1 3 10.1186/s12943-019-1128-6 31906946
112 Shi Y. Fan S. Wu M. Zuo Z. Li X. Jiang L. Shen Q. Xu P. Zeng L. Zhou Y. Huang Y. Yang Z. Zhou J. Gao J. Zhou H. Xu S. Ji H. Shi P. Wu D.D. Yang C. Chen Y. YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat. Commun. 2019 10 1 4892 10.1038/s41467-019-12801-6 31653849
113 Chang G. Shi L. Ye Y. Shi H. Zeng L. Tiwary S. Huse J.T. Huo L. Ma L. Ma Y. Zhang S. Zhu J. Xie V. Li P. Han L. He C. Huang S. YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis. Cancer Cell 2020 38 6 857 871.e7 10.1016/j.ccell.2020.10.004 33125861
114 Einstein J.M. Perelis M. Chaim I.A. Meena J.K. Nussbacher J.K. Tankka A.T. Yee B.A. Li H. Madrigal A.A. Neill N.J. Shankar A. Tyagi S. Westbrook T.F. Yeo G.W. Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer. Mol. Cell 2021 81 15 3048 3064.e9 10.1016/j.molcel.2021.06.014 34216543
115 Zhong L. Liao D. Zhang M. Zeng C. Li X. Zhang R. Ma H. Kang T. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019 442 252 261 10.1016/j.canlet.2018.11.006 30423408
116 Waly A.A. El-Ekiaby N. Assal R.A. Abdelrahman M.M. Hosny K.A. El Tayebi H.M. Esmat G. Breuhahn K. Abdelaziz A.I. Methylation in MIRLET7A3 Gene Induces the Expression of IGF-II and Its mRNA Binding Proteins IGF2BP-2 and 3 in Hepatocellular Carcinoma. Front. Physiol. 2019 9 1918 10.3389/fphys.2018.01918 30733684
117 Zhang L. Wan Y. Zhang Z. Jiang Y. Gu Z. Ma X. Nie S. Yang J. Lang J. Cheng W. Zhu L. IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression. Theranostics 2021 11 3 1100 1114 10.7150/thno.49345 33391523
118 Xu Y. Guo Z. Peng H. Guo L. Wang P. IGF2BP3 promotes cell metastasis and is associated with poor patient survival in nasopharyngeal carcinoma. J. Cell. Mol. Med. 2022 26 2 410 421 10.1111/jcmm.17093 34894048
119 Tan B. Zhou K. Liu W. Prince E. Qing Y. Li Y. Han L. Qin X. Su R. Pokharel S.P. Yang L. Zhao Z. Shen C. Li W. Chen Z. Zhang Z. Deng X. Small A. Wang K. Leung K. Chen C.W. Shen B. Chen J. RNA N 6 -methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer. Theranostics 2022 12 13 5727 5743 10.7150/thno.71872 35966596
120 Su Y. Wang B. Huang J. Huang M. Lin T. YTHDC1 positively regulates PTEN expression and plays a critical role in cisplatin resistance of bladder cancer. Cell Prolif. 2023 56 7 e13404 10.1111/cpr.13404 37070134
121 Song J. You G. Yin X. Zhu G. Wang W. Yu Y. Zhu J. Overexpression of YTHDC2 contributes to the progression of prostate cancer and predicts poor outcomes in patients with prostate cancer. J. Biochem. Mol. Toxicol. 2023 37 4 e23308 10.1002/jbt.23308 36644951
122 Cai Z. Xu H. Bai G. Hu H. Wang D. Li H. Wang Z. ELAVL1 promotes prostate cancer progression by interacting with other m6A regulators. Front. Oncol. 2022 12 939784 10.3389/fonc.2022.939784 35978821
123 Liu H. Li D. Sun L. Qin H. Fan A. Meng L. Graves-Deal R. Glass S.E. Franklin J.L. Liu Q. Wang J. Yeatman T.J. Guo H. Zong H. Jin S. Chen Z. Deng T. Fang Y. Li C. Karijolich J. Patton J.G. Wang X. Nie Y. Fan D. Coffey R.J. Zhao X. Lu Y. Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression. Mol. Cancer 2022 21 1 74 10.1186/s12943-022-01555-3 35279145
124 Fu C. Kou R. Meng J. Jiang D. Zhong R. Dong M. m6A genotypes and prognostic signature for assessing the prognosis of patients with acute myeloid leukemia. BMC Med. Genomics 2023 16 1 191 10.1186/s12920-023-01629-1 37596597
125 Zhuang H. Yu B. Tao D. Xu X. Xu Y. Wang J. Jiao Y. Wang L. The role of m6A methylation in therapy resistance in cancer. Mol. Cancer 2023 22 1 91 10.1186/s12943-023-01782-2 37264402
126 Smolarz B. Durczyński A. Romanowicz H. Szyłło K. Hogendorf P. miRNAs in Cancer (Review of Literature). Int. J. Mol. Sci. 2022 23 5 2805 10.3390/ijms23052805 35269947
127 Yoshida T. Asano Y. Ui-Tei K. Modulation of MicroRNA Processing by Dicer via Its Associated dsRNA Binding Proteins. Noncoding RNA 2021 7 3 57 10.3390/ncrna7030057 34564319
128 Zhang J. Bai R. Li M. Ye H. Wu C. Wang C. Li S. Tan L. Mai D. Li G. Pan L. Zheng Y. Su J. Ye Y. Fu Z. Zheng S. Zuo Z. Liu Z. Zhao Q. Che X. Xie D. Jia W. Zeng M.S. Tan W. Chen R. Xu R.H. Zheng J. Lin D. Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat. Commun. 2019 10 1 1858 10.1038/s41467-019-09712-x 31015415
129 Park Y.M. Hwang S.J. Masuda K. Choi K.M. Jeong M.R. Nam D.H. Gorospe M. Kim H.H. Heterogeneous nuclear ribonucleoprotein C1/C2 controls the metastatic potential of glioblastoma by regulating PDCD4. Mol. Cell. Biol. 2012 32 20 4237 4244 10.1128/MCB.00443-12 22907752
130 Klinge C.M. Piell K.M. Tooley C.S. Rouchka E.C. HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells. Sci. Rep. 2019 9 1 9430 10.1038/s41598-019-45636-8 31263129
131 Hou Y. Zhang Q. Pang W. Hou L. Liang Y. Han X. Luo X. Wang P. Zhang X. Li L. Meng X. YTHDC1-mediated augmentation of miR-30d in repressing pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of Warburg effect. Cell Death Differ. 2021 28 11 3105 3124 10.1038/s41418-021-00804-0 34021267
132 Rong L. Xu Y. Zhang K. Jin L. Liu X. HNRNPA2B1 inhibited SFRP2 and activated Wnt-β/catenin via m6A-mediated miR-106b-5p processing to aggravate stemness in lung adenocarcinoma. Pathol. Res. Pract. 2022 233 153794 10.1016/j.prp.2022.153794 35364458
133 Yi D. Wang R. Shi X. Xu L. Yilihamu Y. Sang J. METTL14 promotes the migration and invasion of breast cancer cells by modulating N6-methyladenosine and hsa-miR-146a-5p expression. Oncol. Rep. 2020 43 5 1375 1386 10.3892/or.2020.7515 32323801
134 Gao C. Wei J. Tang T. Huang Z. Role of microRNA-33a in malignant cells (Review). Oncol. Lett. 2020 20 3 2537 2556 10.3892/ol.2020.11835 32782572
135 Shan Y. Liu Y. Zhao L. Liu B. Li Y. Jia L. MicroRNA-33a and let-7e inhibit human colorectal cancer progression by targeting ST8SIA1. Int. J. Biochem. Cell Biol. 2017 90 48 58 10.1016/j.biocel.2017.07.016 28751193
136 Zhang C. Zhang Y. Ding W. Lin Y. Huang Z. Luo Q. MiR-33a suppresses breast cancer cell proliferation and metastasis by targeting ADAM9 and ROS1. Protein Cell 2015 6 12 881 889 10.1007/s13238-015-0223-8 26507842
137 Su X. Lai T. Tao Y. Zhang Y. Zhao C. Zhou J. Chen E. Zhu M. Zhang S. Wang B. Mao Y. Hu H. miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis. Sci. Rep. 2023 13 1 13587 10.1038/s41598-023-39506-7 37604948
138 Du M. Zhang Y. Mao Y. Mou J. Zhao J. Xue Q. Wang D. Huang J. Gao S. Gao Y. MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA. Biochem. Biophys. Res. Commun. 2017 482 4 582 589 10.1016/j.bbrc.2016.11.077 27856248
139 He L. Chen S. Ying Y. Xie H. Li J. Ma X. Wang W. Shen H. Wang X. Zheng X. Xie L. MicroRNA-501-3p inhibits the proliferation of kidney cancer cells by targeting WTAP. Cancer Med. 2021 10 20 7222 7232 10.1002/cam4.4157 34595849
140 Liu W. Gao X. Chen X. Zhao N. Sun Y. Zou Y. Guan Y. Yang L. Pei X. Wang G. Wang B. Li M. Song W. miR-139-5p loss-mediated wtap activation contributes to hepatocellular carcinoma progression by promoting the epithelial to mesenchymal transition. Front. Oncol. 2021 11 611544 10.3389/fonc.2021.611544 33937023
141 Xue J. Xiao P. Yu X. Zhang X. A positive feedback loop between AlkB homolog 5 and miR-193a-3p promotes growth and metastasis in esophageal squamous cell carcinoma. Hum. Cell 2021 34 2 502 514 10.1007/s13577-020-00458-z 33231844
142 Feng H. Yuan X. Wu S. Yuan Y. Cui L. Lin D. Peng X. Liu X. Wang F. Effects of writers, erasers and readers within miRNA-related m6A modification in cancers. Cell Prolif. 2023 56 1 e13340 10.1111/cpr.13340 36162823
143 Das Mandal S. Ray P.S. Transcriptome-wide analysis reveals spatial correlation between N6-methyladenosine and binding sites of microRNAs and RNA-binding proteins. Genomics 2021 113 1 205 216 10.1016/j.ygeno.2020.12.027 33340693
144 Kanoria S. Rennie W.A. Carmack C.S. Lu J. Ding Y. N 6-methyladenosine enhances post-transcriptional gene regulation by microRNAs. Bioinformatics Advances 2022 2 1 vbab046 10.1093/bioadv/vbab046 35098135
145 He X. Shu Y. RNA N6-methyladenosine modification participates in miR-660/E2F3 axis-mediated inhibition of cell proliferation in gastric cancer. Pathol. Res. Pract. 2019 215 6 152393 10.1016/j.prp.2019.03.021 30914234
146 Zhang M. Xin Y. Circular RNAs: A new frontier for cancer diagnosis and therapy. J. Hematol. Oncol. 2018 11 1 21 10.1186/s13045-018-0569-5 29433541
147 Kristensen L.S. Andersen M.S. Stagsted L.V.W. Ebbesen K.K. Hansen T.B. Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 2019 20 11 675 691 10.1038/s41576-019-0158-7 31395983
148 Sun M. Yang Y. Biological functions and applications of circRNAs—next generation of RNA-based therapy. J. Mol. Cell Biol. 2023 15 5 mjad031 10.1093/jmcb/mjad031 37147015
149 Yang Y. Fan X. Mao M. Song X. Wu P. Zhang Y. Jin Y. Yang Y. Chen L.L. Wang Y. Wong C.C.L. Xiao X. Wang Z. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res. 2017 27 5 626 641 10.1038/cr.2017.31 28281539
150 Chen R.X. Chen X. Xia L.P. Zhang J.X. Pan Z.Z. Ma X.D. Han K. Chen J.W. Judde J.G. Deas O. Wang F. Ma N.F. Guan X. Yun J.P. Wang F.W. Xu R.H. Dan Xie N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis. Nat. Commun. 2019 10 1 4695 10.1038/s41467-019-12651-2 31619685
151 Fan H.N. Chen Z.Y. Chen X.Y. Chen M. Yi Y.C. Zhu J.S. Zhang J. METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis. Mol. Cancer 2022 21 1 51 10.1186/s12943-022-01521-z 35164771
152 Liu H. Lan T. Li H. Xu L. Chen X. Liao H. Chen X. Du J. Cai Y. Wang J. Li X. Huang J. Yuan K. Zeng Y. Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR. Theranostics 2021 11 3 1396 1411 10.7150/thno.53227 33391541
153 Li Z. Yang H.Y. Dai X.Y. Zhang X. Huang Y.Z. Shi L. Wei J.F. Ding Q. CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression. Int. J. Biol. Sci. 2021 17 5 1178 1190 10.7150/ijbs.57783 33867838
154 Chen C. Yuan W. Zhou Q. Shao B. Guo Y. Wang W. Yang S. Guo Y. Zhao L. Dang Q. Yang X. Wang G. Kang Q. Ji Z. Liu J. Sun Z. N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization. Theranostics 2021 11 9 4298 4315 10.7150/thno.51342 33754062
155 Ji F. Lu Y. Chen S. Yu Y. Lin X. Zhu Y. Luo X. IGF2BP2-modified circular RNA circARHGAP12 promotes cervical cancer progression by interacting m6A/FOXM1 manner. Cell Death Discov. 2021 7 1 215 10.1038/s41420-021-00595-w 34392306
156 Guan H. Tian K. Luo W. Li M. m6A-modified circRNA MYO1C participates in the tumor immune surveillance of pancreatic ductal adenocarcinoma through m6A/PD-L1 manner. Cell Death Dis. 2023 14 2 120 10.1038/s41419-023-05570-0 36781839
157 Duan J.L. Chen W. Xie J.J. Zhang M.L. Nie R.C. Liang H. Mei J. Han K. Xiang Z.C. Wang F.W. Teng K. Chen R.X. Deng M.H. Yin Y.X. Zhang N. Xie D. Cai M.Y. A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma. Mol. Cancer 2022 21 1 93 10.1186/s12943-022-01537-5 35366894
158 Wu Q. Yin X. Zhao W. Xu W. Chen L. Molecular mechanism of m6A methylation of circDLC1 mediated by RNA methyltransferase METTL3 in the malignant proliferation of glioma cells. Cell Death Discov. 2022 8 1 229 10.1038/s41420-022-00979-6 35474040
159 Li B. Zhu L. Lu C. Wang C. Wang H. Jin H. Ma X. Cheng Z. Yu C. Wang S. Zuo Q. Zhou Y. Wang J. Yang C. Lv Y. Jiang L. Qin W. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat. Commun. 2021 12 1 295 10.1038/s41467-020-20527-z 33436560
160 Pisignano G. Michael D.C. Visal T.H. Pirlog R. Ladomery M. Calin G.A. Going circular: history, present, and future of circRNAs in cancer. Oncogene 2023 42 38 2783 2800 10.1038/s41388-023-02780-w 37587333
161 Mattick J.S. Amaral P.P. Carninci P. Carpenter S. Chang H.Y. Chen L.L. Chen R. Dean C. Dinger M.E. Fitzgerald K.A. Gingeras T.R. Guttman M. Hirose T. Huarte M. Johnson R. Kanduri C. Kapranov P. Lawrence J.B. Lee J.T. Mendell J.T. Mercer T.R. Moore K.J. Nakagawa S. Rinn J.L. Spector D.L. Ulitsky I. Wan Y. Wilusz J.E. Wu M. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat. Rev. Mol. Cell Biol. 2023 24 6 430 447 10.1038/s41580-022-00566-8 36596869
162 Fatica A. Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat. Rev. Genet. 2014 15 1 7 21 10.1038/nrg3606 24296535
163 Aprile M. Costa V. Cimmino A. Calin G.A. Emerging role of oncogenic long noncoding RNA as cancer biomarkers. Int. J. Cancer 2023 152 5 822 834 10.1002/ijc.34282 36082440
164 Fonseca-Montaño M.A. Vázquez-Santillán K.I. Hidalgo-Miranda A. The current advances of lncRNAs in breast cancer immunobiology research. Front. Immunol. 2023 14 1194300 10.3389/fimmu.2023.1194300 37342324
165 Li J. Momen-Heravi F. Wu X. He K. Mechanism of METTL14 and m6A modification of lncRNA MALAT1 in the proliferation of oral squamous cell carcinoma cells. Oral Dis. 2023 29 5 2012 2026 10.1111/odi.14220 35467063
166 Li S. Jiang F. Chen F. Deng Y. Pan X. Effect of m6A methyltransferase METTL3 -mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer. J. Biochem. Mol. Toxicol. 2022 36 1 e22922 10.1002/jbt.22922 34964205
167 Lee J. Wu Y. Harada B.T. Li Y. Zhao J. He C. Ma Y. Wu X. N 6 -methyladenosine modification of lncRNA Pvt1 governs epidermal stemness. EMBO J. 2021 40 8 e106276 10.15252/embj.2020106276 33729590
168 Chen S. Zhou L. Wang Y. ALKBH5-mediated m6A demethylation of lncRNA PVT1 plays an oncogenic role in osteosarcoma. Cancer Cell Int. 2020 20 1 34 10.1186/s12935-020-1105-6 32021563
169 Hu Y. Lv F. Li N. Yuan X. Zhang L. Zhao S. Jin L. Qiu Y. Long noncoding RNA MEG3 inhibits oral squamous cell carcinoma progression via GATA3. FEBS Open Bio 2023 13 1 195 208 10.1002/2211-5463.13532 36468944
170 Li K. Gong Q. Xiang X.D. Guo G. Liu J. Zhao L. Li J. Chen N. Li H. Zhang L.J. Zhou C.Y. Wang Z.Y. Zhuang L. HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis. J. Transl. Med. 2023 21 1 382 10.1186/s12967-023-04190-8 37308993
171 Ni W. Yao S. Zhou Y. Liu Y. Huang P. Zhou A. Liu J. Che L. Li J. Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m6A reader YTHDF3. Mol. Cancer 2019 18 1 143 10.1186/s12943-019-1079-y 31619268
172 Zhu P. He F. Hou Y. Tu G. Li Q. Jin T. Zeng H. Qin Y. Wan X. Qiao Y. Qiu Y. Teng Y. Liu M. A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability. Oncogene 2021 40 9 1609 1627 10.1038/s41388-020-01638-9 33469161
173 Ma F. Liu X. Zhou S. Li W. Liu C. Chadwick M. Qian C. Long non-coding RNA FGF13-AS1 inhibits glycolysis and stemness properties of breast cancer cells through FGF13-AS1/IGF2BPs/Myc feedback loop. Cancer Lett. 2019 450 63 75 10.1016/j.canlet.2019.02.008 30771425
174 Zuo L. Su H. Zhang Q. Wu W. Zeng Y. Li X. Xiong J. Chen L. Zhou Y. Comprehensive analysis of lncRNAs N6-methyladenosine modification in colorectal cancer. Aging (Albany NY) 2021 13 3 4182 4198 10.18632/aging.202383 33493136
175 Zeng H. Xu Y. Xu S. Jin L. Shen Y. Rajan K.C. Bhandari A. Xia E. Construction and Analysis of a Colorectal Cancer Prognostic Model Based on N6-Methyladenosine-Related lncRNAs. Front. Cell Dev. Biol. 2021 9 698388 10.3389/fcell.2021.698388 34490250
176 Song W. Ren J. Yuan W. Xiang R. Ge Y. Fu T. N6-Methyladenosine-Related lncRNA Signature Predicts the Overall Survival of Colorectal Cancer Patients. Genes (Basel) 2021 12 9 1375 10.3390/genes12091375 34573357
177 Wang H. Meng Q. Ma B. Characterization of the Prognostic m6A-Related lncRNA Signature in Gastric Cancer. Front. Oncol. 2021 11 630260 10.3389/fonc.2021.630260 33928026
178 Tu Z. Wu L. Wang P. Hu Q. Tao C. Li K. Huang K. Zhu X. N6-Methylandenosine-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Lower-Grade Glioma Patients. Front. Cell Dev. Biol. 2020 8 642 10.3389/fcell.2020.00642 32793593
179 Weng L. Qiu K. Gao W. Shi C. Shu F. LncRNA PCGEM1 accelerates non-small cell lung cancer progression via sponging miR-433-3p to upregulate WTAP. BMC Pulm. Med. 2020 20 1 213 10.1186/s12890-020-01240-5 32787827
180 Zhou X. Chang Y. Zhu L. Shen C. Qian J. Chang R. LINC00839/miR-144-3p/WTAP (WT1 Associated protein) axis is involved in regulating hepatocellular carcinoma progression. Bioengineered 2021 12 2 10849 10861 10.1080/21655979.2021.1990578 34634995
181 Ge J. Liu M. Zhang Y. Xie L. Shi Z. Wang G. SNHG10/miR-141-3p/WTAP axis promotes osteosarcoma proliferation and migration. J. Biochem. Mol. Toxicol. 2022 36 6 e23031 10.1002/jbt.23031 35274397
182 Huang T. Cao L. Feng N. Xu B. Dong Y. Wang M. N 6 -methyladenosine (m 6 A)-mediated lncRNA DLGAP1-AS1enhances breast canceradriamycin resistance through miR-299-3p/WTAP feedback loop. Bioengineered 2021 12 2 10935 10944 10.1080/21655979.2021.2000198 34866525
183 Bedi R.K. Huang D. Li Y. Caflisch A. Structure-Based Design of Inhibitors of the m 6 A-RNA Writer Enzyme METTL3. ACS Bio & Med Chem Au 2023 3 4 359 370 10.1021/acsbiomedchemau.3c00023 37599794
184 Moroz-Omori E.V. Huang D. Kumar Bedi R. Cheriyamkunnel S.J. Bochenkova E. Dolbois A. Rzeczkowski M.D. Li Y. Wiedmer L. Caflisch A. METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes. ChemMedChem 2021 16 19 3035 3043 10.1002/cmdc.202100291 34237194
185 Zhang L. Ren T. Wang Z. Wang R. Chang J. Comparative study of the binding of 3 flavonoids to the fat mass and obesity-associated protein by spectroscopy and molecular modeling. J. Mol. Recognit. 2017 30 6 e2606 10.1002/jmr.2606 28058739
186 Chen B. Ye F. Yu L. Jia G. Huang X. Zhang X. Peng S. Chen K. Wang M. Gong S. Zhang R. Yin J. Li H. Yang Y. Liu H. Zhang J. Zhang H. Zhang A. Jiang H. Luo C. Yang C.G. Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor. J. Am. Chem. Soc. 2012 134 43 17963 17971 10.1021/ja3064149 23045983
187 Yu J. Chen M. Huang H. Zhu J. Song H. Zhu J. Park J. Ji S.J. Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res. 2018 46 3 1412 1423 10.1093/nar/gkx1182 29186567
188 Huang Y. Yan J. Li Q. Li J. Gong S. Zhou H. Gan J. Jiang H. Jia G.F. Luo C. Yang C.G. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 2015 43 1 373 384 10.1093/nar/gku1276 25452335
189 Yankova E. Blackaby W. Albertella M. Rak J. De Braekeleer E. Tsagkogeorga G. Pilka E.S. Aspris D. Leggate D. Hendrick A.G. Webster N.A. Andrews B. Fosbeary R. Guest P. Irigoyen N. Eleftheriou M. Gozdecka M. Dias J.M.L. Bannister A.J. Vick B. Jeremias I. Vassiliou G.S. Rausch O. Tzelepis K. Kouzarides T. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature 2021 593 7860 597 601 10.1038/s41586-021-03536-w 33902106
190 Zaccara S. Jaffrey S.R. A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA. Cell 2020 181 7 1582 1595.e18 10.1016/j.cell.2020.05.012 32492408
191 Deng S. Zhang J. Su J. Zuo Z. Zeng L. Liu K. Zheng Y. Huang X. Bai R. Zhuang L. Ye Y. Li M. Pan L. Deng J. Wu G. Li R. Zhang S. Wu C. Lin D. Chen J. Zheng J. RNA m6A regulates transcription via DNA demethylation and chromatin accessibility. Nat. Genet. 2022 54 9 1427 1437 10.1038/s41588-022-01173-1 36071173
