==== Front Clin Nutr ResClin Nutr ResCNRClinical Nutrition Research2287-37322287-3740Korean Society of Clinical Nutrition 10.7762/cnr.2018.7.3.153Review ArticleLinks between Serine Biosynthesis Pathway and Epigenetics in Cancer Metabolism https://orcid.org/0000-0001-6675-4292Kim HaEun https://orcid.org/0000-0001-6999-4996Park Yoon Jung Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea.Correspondence to Yoon Jung Park. Department of Nutritional Science and Food Management, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea. park.yoonjung@ewha.ac.kr7 2018 26 7 2018 7 3 153 160 23 4 2018 19 7 2018 19 7 2018 Copyright © 2018. The Korean Society of Clinical Nutrition2018The Korean Society of Clinical NutritionThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C. On the other hand, SSP also influences epigenetic landscape such as methylation status of nucleic acids and histone proteins via affecting S-adenosyl methionine production. In the review, we highlight recent evidences on interactions between SSP and epigenetic regulation in cancer. It may provide an insight on roles and regulation of SSP in cancer metabolism and the potential of serine metabolism for cancer therapy. SerineEpigeneticsCancer, MetabolismBiosynthesisNational Research Foundation of Koreahttp://dx.doi.org/10.13039/5011000037252018R1D1A1B07051274Brain Korea 21 PLUS22A20130012143 ==== Body INTRODUCTION Cancer is one of the leading causes of death worldwide and its incidence is dramatically increasing. The last few decades have witnessed significant progress in understanding of molecular and cellular basis of cancer cells. Metabolic alteration is one of the cancer hallmarks [1]. Metabolism in cancer cells is unique to support rapid proliferation, often making the environment under lack of nutrients and oxygen [234]. The cancer-specific metabolism provides a potential as therapeutic targets [5]. Serine metabolism is recently highlighted because of the roles in supporting tumor growth. Although the molecular mechanism is not fully understood, one possibility is through affecting production of S-adenosyl methionine (SAM), which is the substrate of DNA and histone methyltransferases. It suggests that serine metabolism directly or indirectly influence epigenetic alterations in cells [6]. Epigenetic mechanism contributes to altered gene function and cancer progression and its reversible nature has highlighted the application of epigenetic therapy [7]. Therefore, in this review, we focus on serine metabolism and its regulation by or on epigenetic modifiers in cancer cells. CANCER METABOLISM Cancer cells proliferate in 3 dimensional multicellular masses and the growing tumors as aggregation of cancer cells face insufficient supply of oxygen and nutrients. The hypoxic condition stimulates to form new blood vessels, so-called angiogenesis [8] and enhances nutrient uptake into cancer cells to satisfy metabolic requirements [9]. In addition, intracellular energetic and biosynthetic pathways are altered to sustain cell proliferation [9]. The Warburg effect is the most well-known example of altered glucose metabolism of cancer cells [10]. Normal cells use glucose to allow for energy production in a form of ATP through the oxidation of its carbon bonds. In contrast, cancer cells use glucose mainly by glycolysis, which produces lactate even in the presence of oxygen, instead of the efficient oxidative phosphorylation [10]. The aerobic glycolysis produces ATP at a fast rate than oxidative phosphorylation does, in spite of low efficiency in ATP yield per molecule of glucose [11]. However, glycolysis in cancer cells is not essential to contribute to ATP production since the average contribution of ATP from glycolysis is only 17% [12]. Currently, it is thought that aerobic glycolysis fulfills needs in cancer cells to support macromolecule biosynthesis, beyond ATP production [13]. High demand of macromolecule biosynthesis in proliferating cancer cells also requires precursors, derived from amino acids such as serine and glycine [14]. SERINE-GLYCINE METABOLISM IN CANCER CELLS Serine synthesis pathway (SSP) Cancer cells rapidly consume and utilize serine as an intermediate metabolite [14]. Serine is synthesized through SSP, which begins with the glycolytic intermediate 3-phosphoglycerate (3-PG) (Figure 1). 3-PG is converted to 3-hydroxypyruvate by the action of the enzyme, phosphoglycerate dehydrogenase (PHGDH) and then 3-hydroxypyruvate (3P-pyruvate) takes part in a transamination reaction with glutamate catalyzed by the enzyme, phosphoserine aminotransferase (PSAT1), resulting in production of phosphoserine (3P-serine) and alpha-ketoglutarate. Phosphoserine is dephosphorylated by the action of phosphoserine phosphatase (PSPH) and produces serine [15]. Serine is mutually converted into glycine by serine hydroxymethyltransferases (SHMTs), which have two isoforms; SHMT1 in cytoplasm and SHMT2 in mitochondria [16]. SHMTs bridge between SSP and one-carbon metabolism. One-carbon metabolism involves a complex of metabolic network based on biochemical reactions of folate by the one-carbon groups [171819]. Folate, one of the B vitamins, is reduced by activation of dihydrofolate reductase (DHFR), resulting in the generation of tetrahydrofolate (THF) [1920]. SHMTs, especially SHMT2, transfer a carbon unit from serine to THF to form methylene-THF, initiating the folate cycle. The folate cycle is then coupled to the methionine cycle through methyl-THF (mTHF). Furthermore, the adenylation of methionine produces S-adenosylmethionine (SAM) which functions as a methyl donor for other metabolic pathways that require methyl moieties, including histone, DNA and RNA methylation [2122]. Figure 1 Serine-glycine biosynthesis pathway. Serine is biosynthesized from 3-PG by PHGDH, PSAT1, and PSPH. Biosynthesized serine can be converted into glycine by SHMT1/2. This pathway provides precursors for TCA cycle and antioxidant and purine biosynthesis. 3-PG, 3-phosphoglycerate; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SHMT, serine hydroxymethyltransferase; TCA, tricarboxylic acid; THF, tetrahydrofolate; mTHF, methyl-THF. Serine and glycine in cancer cells Serine and glycine are involved in several biological functions such as glycolysis [23], glutathione (GSH) and nucleotide production [14], and thus are closely associated with proliferation of cancer cell [14]. Serine metabolism and glycolysis are connected by pyruvate kinase M2 isoform (PKM2) [23]. Serine is the allosteric activator of PKM2. PKM2 is inactivated under serine deprivation condition, resulting in an accumulation of upstream glycolytic intermediates. Increased glycolytic intermediates, such as 3-PG, facilitate for metabolic diversion into the SSP [23]. To compensate the low level of glycolysis following PKM2 inhibition, the cells divert a flux of pyruvate into mitochondria to make more energy through tricarboxylic acid (TCA) cycle [23]. Glycine, which is biosynthetically linked with serine, is one of components of GSH, together with glutamate and cysteine. GSH is involved in protection of major cellular components against reactive oxygen species [24] and sensitivity against chemotherapeutic agents such as alkylating agents. Besides, serine and glycine metabolism are involved in nucleotide production, which is highly demanded in cancer cells. Serine is an important precursor of purine and pyrimidine nucleotide biosynthesis in mammalian cells and glycine converted from serine serves as both a carbon and nitrogen source for purine-ring biosynthesis [25]. Serine metabolism is upregulated in many tumors [152627] and PHGDH is the key enzyme of the SSP flux [1528]. The gene encoding PHGDH, located on chromosome 1p12, is mostly amplified in human cancer samples, including breast cancer and melanoma [2930]. Also, colonic tumor tissues have been reported to show significantly increased expression of PHGDH and PSAT, compared to paired normal tissue [31]. In estrogen receptor-negative breast cancer cells, high levels of PHGDH and PSAT were associated with poor prognosis with shorter time to relapse, shorter overall survival time, higher tumor grade, and higher proliferative marker levels [26]. Furthermore, higher expression of PHGDH in glioma and cervical cancer was associated with higher tumor grade [3233]. EPIGENETIC AND SERINE METABOLISM Epigenetic alteration in cancer Epigenetics is the study of changes in gene regulation through DNA methylation, histone modification, and non-coding RNA without changes in DNA sequence [3435]. Cytosine in DNA is modified by an addition of a methyl group by DNA methyltransferases (DNMTs) and that produces methylated DNA [36]. DNA methylation is important in cellular differentiation, establishment of genomic imprinting, and regulation of genome stability [37]. Histone modification is another well-known epigenetic mechanism. The N-terminal tails of histones go through various posttranslational covalent modifications such as methylation, acetylation, ubiquitylation, sumoylation, and phosphorylation on specific residues [38]. The modifications activate or repress gene expression by modulating chromatin structure, depending on modified residues and covalently modifying groups. Aberrant epigenetic changes are considered as a hallmark of cancer [39]. It has emerged that human cancer cells carry epigenetic abnormalities beside genetic alterations and many of the epigenetic alterations play key roles in cancer initiation and progression [404142]. For examples, DNA methyltransferase 3A (DNMT3A), one of major DNMTs, shows somatic mutations in 22% of cases of acute myeloid leukemia (AML) and patients with DNMT3A mutations are associated with shorter overall survival [43]. Similarly, histone methylation has been connected to tumorigenesis. Aberrant patterns of histone methylation by overexpression of histone methyltransferases, EZH2 and EHMT2, are strongly associated with multiple types of cancer [44454647]. Serine metabolism and epigenetic changes Serine metabolism is linked to one-carbon metabolism, which influences epigenetic patterns through production of SAM. SAM derived from methionine is the major methyl donor in cellular methyl transfer process including DNA/RNA methylation [21]. Although serine is not directly involved in DNA/RNA methylation, serine starvation reduces DNA/RNA methylation levels in cancer cells via lack of regeneration of methionine from homocysteine (Table 1) [48]. Table 1 Summary of the relationships between serine metabolism and epigenetics Relationships Regulator Results Ref. Serine metabolism → epigenetics Serine Serine regenerates methionine from homocysteine resulting in contribution to DNA/RNA methylation [48] LKB1 LKB1 loss restricts serine metabolism and it causes lower production of SAM leading to lower 5mC level in KRAS mutation cells [49] Epigenetics → serine metabolism EHMT2 Decrease in SSP enzymes level and serine level in EHMT2 inhibition via decreasing H3K9me1 and increasing H3K9me2 at the promoter of SSP enzymes [51] KDM4C Increase in ATF4 mRNA level by lowering H3K9me3 at the promoter of ATF4 leading to increase in SSP enzymes mRNA level [53] LKB1, liver kinase B1; SAM, S-adenosyl methionine; KRAS, Kirsten rat sarcoma viral oncogene homolog proto-oncogene; SSP, serine synthesis pathway; H3K9, histone H3 lysine 9. The relationship between serine metabolism and DNA methylation has been suggested in the liver kinase B1 (LKB1) deficient model (Table 1) [49]. The cooperation of Kirsten rat sarcoma viral oncogene homolog (KRAS) proto-oncogene (KRAS) activation and LKB1 inactivation results in the synergic oncogenic effect by altering cellular metabolism. In the cells with KRAS activation, LKB1 loss dramatically induces SSP by elevating PSAT1, PSPH, and SHMTs, leading to high SAM production. Furthermore, LKB1 loss increases the expression of methyltransferases, such as DNA methyltransferase 1 (DNMT1) and DNMT3A, resulting in DNA hypermethylation. LKB1 directly regulates 14 kinases related to AMP-activated protein kinase (AMPK), which has a central role in nutrient sensing and reprograming of cell metabolism [50]. LKB1 loss-induced alteration of SSP and DNA methylation takes place in an AMPK-mTOR-dependent manner [49]. The results from the LKB1 model emphasize that serine metabolism-coupled SAM generation directly influences regulation of DNA methylation to support tumorigenesis in cancer cells. Epigenetic regulation on SSP There is limited evidence to show that epigenetic modifiers directly regulate SSP. However, a few studies recently suggested several possibilities (Table 1) [5152]. Firstly, EHMT2 regulates SSP [51]. Loss of EHMT2 by activity inhibition or silencing decreases expression of SSP-related genes, PHGDH, PSAT1, PSPH, and SHMT1/2, by reducing mono-methylation and increasing di-methylation at histone H3 lysine 9 (H3K9). In turn, the suppressed SSP reduces the concentration of serine and glycine, leading to cell death. Thus, EHMT2 in cancer provides serine and glycine to support cell proliferation by increasing expression of SSP-related genes. Another epigenetic modifier that regulates SSP is KDM4C. KDM4C is a histone demethylase, targeting histone H3K9. It acts on H3K9 tri-methylation at the promoter of the ATF4 gene and activates the expression [53]. ATF4 is the master regulator of amino acid metabolism including genes encoding SSP enzymes, PHGDH, PSAT1, and PSPH [54]. The results indicate that KDM4C induces SSP by transcriptional upregulation of ATF4 [52]. CONCLUSION Serine metabolism plays a significant role in proliferating cancer cells by providing precursors for macromolecule biosynthesis. SSP-dependent SAM generation affects epigenetic patterns, in particular changes in methylation on DNA, RNA, and histones, leading to transcriptional changes of oncogenes and tumor suppressor genes. On the other hand, genes encoding SSP enzymes are also directly regulated by epigenetic enzymes, catalyzing acquisition or removal of histone methylation. The evidences suggest that the interactions between SSP and epigenetic regulation contribute to cancer-specific metabolism to sustain rapid proliferation. Further investigations on the regulation of SSP and epigenetic modifiers will shed light upon their potentials as anticancer therapeutic targets. Funding: This study was supported by Basic Science Research Programs through the National Research Foundation of Korea (2018R1D1A1B07051274). HaEun Kim was supported by Brain Korea 21 PLUS Project (22A20130012143). Conflict of Interest: The authors declare that they have no competing interests. ==== Refs 1 Hanahan D Weinberg RA Hallmarks of cancer: the next generation Cell 2011 144 646 674 21376230 2 Carmeliet P Dor Y Herbert JM Fukumura D Brusselmans K Dewerchin M Neeman M Bono F Abramovitch R Maxwell P Koch CJ Ratcliffe P Moons L Jain RK Collen D Keshert E Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis Nature 1998 394 485 490 9697772 3 Bertout JA Patel SA Simon MC The impact of O2 availability on human cancer Nat Rev Cancer 2008 8 967 975 18987634 4 Semenza GL HIF-1: upstream and downstream of cancer metabolism Curr Opin Genet Dev 2010 20 51 56 19942427 5 Luengo A Gui DY Vander Heiden MG Targeting metabolism for cancer therapy Cell Chem Biol 2017 24 1161 1180 28938091 6 Mattaini KR Sullivan MR Vander Heiden MG The importance of serine metabolism in cancer J Cell Biol 2016 214 249 257 27458133 7 Sharma S Kelly TK Jones PA Epigenetics in cancer Carcinogenesis 2010 31 27 36 19752007 8 Greenblatt M Shubi P Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique J Natl Cancer Inst 1968 41 111 124 5662020 9 Boroughs LK DeBerardinis RJ Metabolic pathways promoting cancer cell survival and growth Nat Cell Biol 2015 17 351 359 25774832 10 Warburg O On the origin of cancer cells Science 1956 123 309 314 13298683 11 Pfeiffer T Schuster S Bonhoeffer S Cooperation and competition in the evolution of ATP-producing pathways Science 2001 292 504 507 11283355 12 Zu XL Guppy M Cancer metabolism: facts, fantasy, and fiction Biochem Biophys Res Commun 2004 313 459 465 14697210 13 Vander Heiden MG Cantley LC Thompson CB Understanding the Warburg effect: the metabolic requirements of cell proliferation Science 2009 324 1029 1033 19460998 14 Locasale JW Serine, glycine and one-carbon units: cancer metabolism in full circle Nat Rev Cancer 2013 13 572 583 23822983 15 Snell K Enzymes of serine metabolism in normal, developing and neoplastic rat tissues Adv Enzyme Regul 1984 22 325 400 6089514 16 Appaji Rao N Ambili M Jala VR Subramanya HS Savithri HS Structure-function relationship in serine hydroxymethyltransferase Biochim Biophys Acta 2003 1647 24 29 12686103 17 Shane B Stokstad EL Vitamin B12-folate interrelationships Annu Rev Nutr 1985 5 115 141 3927946 18 Stipanuk MH Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine Annu Rev Nutr 2004 24 539 577 15189131 19 Stover PJ Field MS Trafficking of intracellular folates Adv Nutr 2011 2 325 331 22332074 20 Amelio I Cutruzzolá F Antonov A Agostini M Melino G Serine and glycine metabolism in cancer Trends Biochem Sci 2014 39 191 198 24657017 21 Cantoni GL The nature of the active methyl donor formed enzymatically from L-methionine and adenosinetriphosphate J Am Chem Soc 1952 74 2942 2943 22 Teperino R Schoonjans K Auwerx J Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab 2010 12 321 327 20889125 23 Chaneton B Hillmann P Zheng L Martin AC Maddocks OD Chokkathukalam A Coyle JE Jankevics A Holding FP Vousden KH Frezza C O'Reilly M Gottlieb E Serine is a natural ligand and allosteric activator of pyruvate kinase M2 Nature 2012 491 458 462 23064226 24 Pompella A Visvikis A Paolicchi A De Tata V Casini AF The changing faces of glutathione, a cellular protagonist Biochem Pharmacol 2003 66 1499 1503 14555227 25 Snell K Natsumeda Y Weber G The modulation of serine metabolism in hepatoma 3924A during different phases of cellular proliferation in culture Biochem J 1987 245 609 612 3117048 26 Pollari S Käkönen SM Edgren H Wolf M Kohonen P Sara H Guise T Nees M Kallioniemi O Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis Breast Cancer Res Treat 2011 125 421 430 20352489 27 Locasale JW Grassian AR Melman T Lyssiotis CA Mattaini KR Bass AJ Heffron G Metallo CM Muranen T Sharfi H Sasaki AT Anastasiou D Mullarky E Vokes NI Sasaki M Beroukhim R Stephanopoulos G Ligon AH Meyerson M Richardson AL Chin L Wagner G Asara JM Brugge JS Cantley LC Vander Heiden MG Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis Nat Genet 2011 43 869 874 21804546 28 Snell K Weber G Enzymic imbalance in serine metabolism in rat hepatomas Biochem J 1986 233 617 620 3082329 29 Possemato R Marks KM Shaul YD Pacold ME Kim D Birsoy K Sethumadhavan S Woo HK Jang HG Jha AK Chen WW Barrett FG Stransky N Tsun ZY Cowley GS Barretina J Kalaany NY Hsu PP Ottina K Chan AM Yuan B Garraway LA Root DE Mino-Kenudson M Brachtel EF Driggers EM Sabatini DM Functional genomics reveal that the serine synthesis pathway is essential in breast cancer Nature 2011 476 346 350 21760589 30 Beroukhim R Mermel CH Porter D Wei G Raychaudhuri S Donovan J Barretina J Boehm JS Dobson J Urashima M Mc Henry KT Pinchback RM Ligon AH Cho YJ Haery L Greulich H Reich M Winckler W Lawrence MS Weir BA Tanaka KE Chiang DY Bass AJ Loo A Hoffman C Prensner J Liefeld T Gao Q Yecies D Signoretti S Maher E Kaye FJ Sasaki H Tepper JE Fletcher JA Tabernero J Baselga J Tsao MS Demichelis F Rubin MA Janne PA Daly MJ Nucera C Levine RL Ebert BL Gabriel S Rustgi AK Antonescu CR Ladanyi M Letai A Garraway LA Loda M Beer DG True LD Okamoto A Pomeroy SL Singer S Golub TR Lander ES Getz G Sellers WR Meyerson M The landscape of somatic copy-number alteration across human cancers Nature 2010 463 899 905 20164920 31 Yoon S Kim JG Seo AN Park SY Kim HJ Park JS Choi GS Jeong JY Jun Y Yoon GS Kang BW Clinical implication of serine metabolism-associated enzymes in colon cancer Oncology 2015 89 351 359 26439504 32 Liu J Guo S Li Q Yang L Xia Z Zhang L Huang Z Zhang N Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1 J Neurooncol 2013 111 245 255 23229761 33 Jing Z Heng W Aiping D Yafei Q Shulan Z Expression and clinical significance of phosphoglycerate dehydrogenase and squamous cell carcinoma antigen in cervical cancer Int J Gynecol Cancer 2013 23 1465 1469 24247658 34 Waddington CH The epigenotype. 1942 Int J Epidemiol 2012 41 10 13 22186258 35 Wu CT Morris JR Genes, genetics, and epigenetics: a correspondence Science 2001 293 1103 1105 11498582 36 Robertson KD DNA methylation and human disease Nat Rev Genet 2005 6 597 610 16136652 37 Reik W Stability and flexibility of epigenetic gene regulation in mammalian development Nature 2007 447 425 432 17522676 38 Kouzarides T Chromatin modifications and their function Cell 2007 128 693 705 17320507 39 Flavahan WA Gaskell E Bernstein BE Epigenetic plasticity and the hallmarks of cancer Science 2017 357 eaal2380 28729483 40 Jones PA Baylin SB The fundamental role of epigenetic events in cancer Nat Rev Genet 2002 3 415 428 12042769 41 Jones PA Baylin SB The epigenomics of cancer Cell 2007 128 683 692 17320506 42 Lindroth AM Park YJ Plass C Epigenetic reprogramming in cancer Meissner A Walter J Epigenetic mechanisms in cellular reprogramming Berlin Springer 2015 193 223 43 Ley TJ Ding L Walter MJ McLellan MD Lamprecht T Larson DE Kandoth C Payton JE Baty J Welch J Harris CC Lichti CF Townsend RR Fulton RS Dooling DJ Koboldt DC Schmidt H Zhang Q Osborne JR Lin L O'Laughlin M McMichael JF Delehaunty KD McGrath SD Fulton LA Magrini VJ Vickery TL Hundal J Cook LL Conyers JJ Swift GW Reed JP Alldredge PA Wylie T Walker J Kalicki J Watson MA Heath S Shannon WD Varghese N Nagarajan R Westervelt P Tomasson MH Link DC Graubert TA DiPersio JF Mardis ER Wilson RK DNMT3A mutations in acute myeloid leukemia N Engl J Med 2010 363 2424 2433 21067377 44 Varambally S Dhanasekaran SM Zhou M Barrette TR Kumar-Sinha C Sanda MG Ghosh D Pienta KJ Sewalt RG Otte AP Rubin MA Chinnaiyan AM The polycomb group protein EZH2 is involved in progression of prostate cancer Nature 2002 419 624 629 12374981 45 Kleer CG Cao Q Varambally S Shen R Ota I Tomlins SA Ghosh D Sewalt RG Otte AP Hayes DF Sabel MS Livant D Weiss SJ Rubin MA Chinnaiyan AM EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells Proc Natl Acad Sci U S A 2003 100 11606 11611 14500907 46 Hua KT Wang MY Chen MW Wei LH Chen CK Ko CH Jeng YM Sung PL Jan YH Hsiao M Kuo ML Yen ML The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis Mol Cancer 2014 13 189 25115793 47 Casciello F Al-Ejeh F Kelly G Brennan DJ Ngiow SF Young A Stoll T Windloch K Hill MM Smyth MJ Gannon F Lee JS G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis Proc Natl Acad Sci U S A 2017 114 7077 7082 28630300 48 Maddocks OD Labuschagne CF Adams PD Vousden KH Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells Mol Cell 2016 61 210 221 26774282 49 Kottakis F Nicolay BN Roumane A Karnik R Gu H Nagle JM Boukhali M Hayward MC Li YY Chen T Liesa M Hammerman PS Wong KK Hayes DN Shirihai OS Dyson NJ Haas W Meissner A Bardeesy N LKB1 loss links serine metabolism to DNA methylation and tumorigenesis Nature 2016 539 390 395 27799657 50 Shackelford DB Shaw RJ The LKB1-AMPK pathway: metabolism and growth control in tumour suppression Nat Rev Cancer 2009 9 563 575 19629071 51 Ding J Li T Wang X Zhao E Choi JH Yang L Zha Y Dong Z Huang S Asara JM Cui H Ding HF The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation Cell Metab 2013 18 896 907 24315373 52 DeNicola GM Chen PH Mullarky E Sudderth JA Hu Z Wu D Tang H Xie Y Asara JM Huffman KE Wistuba II Minna JD DeBerardinis RJ Cantley LC NRF2 regulates serine biosynthesis in non-small cell lung cancer Nat Genet 2015 47 1475 1481 26482881 53 Zhao E Ding J Xia Y Liu M Ye B Choi JH Yan C Dong Z Huang S Zha Y Yang L Cui H Ding HF KDM4C and ATF4 cooperate in transcriptional control of amino acid metabolism Cell Reports 2016 14 506 519 26774480 54 Adams CM Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids J Biol Chem 2007 282 16744 16753 17430894