Epigenetic regulation in cancer

Abstract

Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.

Keywords

cancer metastasis / epigenetics / tumor microenvironment / tumorigenesis

References

[1] Bates SE. Epigenetic therapies for cancer. N Engl J Med. 2020;383(7):650-663.

[2] Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018;378(14):1323-1334.

[3] Sacchetti A, Teeuwssen M, Verhagen M, et al. Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer. Elife. 2021;10:e61461.

[4] Chang CA, Jen J, Jiang S, et al. Ontogeny and vulnerabilities of drug-tolerant persisters in HER2+ breast cancer. Cancer Discov. 2022;12(4):1022-1045.

[5] Jia D, Jolly MK, Kulkarni P, Levine H. Phenotypic plasticity and cell fate decisions in cancer: insights from dynamical systems theory. Cancers. 2017;9(7):70.

[6] Feinberg AP, Koldobskiy MA, Göndör A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17(5):284-299.

[7] Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31-46.

[8] Versteege I, Sévenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394(6689):203-206.

[9] Lee RS, Stewart C, Carter SL, et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest. 2012;122(8):2983-2988.

[10] Chen JF, Yan Q. The roles of epigenetics in cancer progression and metastasis. Biochem J. 2021;478(17):3373-3393.

[11] Nam AS, Chaligne R, Landau DA. Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics. Nat Rev Genet. 2021;22(1):3-18.

[12] Singh M, Kumar V, Sehrawat N, et al. Current paradigms in epigenetic anticancer therapeutics and future challenges. Semin Cancer Biol. 2022;83:422-440.

[13] Feinberg AP, Levchenko A. Epigenetics as a mediator of plasticity in cancer. Science. 2023;379(6632):eaaw3835.

[14] Jerkovic I, Cavalli G. Understanding 3D genome organization by multidisciplinary methods. Nat Rev Mol Cell Biol. 2021;22(8):511-528.

[15] Li E, Zhang Y. DNA methylation in mammals. Cold Spring Harb Perspect Biol. 2014;6(5):a019133.

[16] Skvortsova K, Stirzaker C, Taberlay P. The DNA methylation landscape in cancer. Essays Biochem. 2019;63(6):797-811.

[17] Greenberg MVC, Bourc'his D. The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol. 2019;20(10):590-607.

[18] Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19(2):81-92.

[19] Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517-534.

[20] Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30(7):733-750.

[21] Chen Z-X, Riggs AD. DNA methylation and demethylation in mammals. J Biol Chem. 2011;286(21):18347-18353.

[22] Bray JK, Dawlaty MM, Verma A, Maitra A. Roles and regulations of TET enzymes in solid tumors. Trends Cancer. 2021;7(7):635-646.

[23] Thirlwell C, Eymard M, Feber A, et al. Genome-wide DNA methylation analysis of archival formalin-fixed paraffin-embedded tissue using the Illumina Infinium HumanMethylation27 BeadChip. Methods. 2010;52(3):248-254.

[24] Ma F, Jiang S, Zhang CY. Recent advances in histone modification and histone modifying enzyme assays. Expert Rev Mol Diagn. 2019;19(1):27-36.

[25] Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol. 2007;14(11):1008-1016.

[26] Kebede AF, Schneider R, Daujat S. Novel types and sites of histone modifications emerge as players in the transcriptional regulation contest. FEBS J. 2015;282(9):1658-1674.

[27] Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12-27.

[28] Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381-395.

[29] Michalak EM, Burr ML, Bannister AJ, Dawson MA. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Biol. 2019;20(10):573-589.

[30] Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005;6(11):838-849.

[31] Allfrey VG, Mirsky AE. Structural modifications of histones and their possible role in the regulation of RNA synthesis. Science. 1964;144(3618):559.

[32] Rea S, Eisenhaber F, O'Carroll D, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000;406(6796):593-599.

[33] Dillon SC, Zhang X, Trievel RC, Cheng X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 2005;6(8):227.

[34] Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439(7078):811-816.

[35] Karytinos A, Forneris F, Profumo A, et al. A novel mammalian flavin-dependent histone demethylase. J Biol Chem. 2009;284(26):17775-17782.

[36] Chi P, Allis CD, Wang GG. Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010;10(7):457-469.

[37] Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012;48(4):491-507.

[38] Chandrasekharan MB, Huang F, Sun ZW. Histone H2B ubiquitination and beyond: regulation of nucleosome stability, chromatin dynamics and the trans-histone H3 methylation. Epigenetics. 2010;5(6):460-468.

[39] Dang F, Wei W. Targeting the acetylation signaling pathway in cancer therapy. Semin Cancer Biol. 2022;85:209-218.

[40] Gujral P, Mahajan V, Lissaman AC, Ponnampalam AP. Histone acetylation and the role of histone deacetylases in normal cyclic endometrium. Reprod Biol Endocrinol. 2020;18(1):84.

[41] Tan T, Shi P, Abbas MN, et al. Epigenetic modification regulates tumor progression and metastasis through EMT (review). Int J Oncol. 2022;60(6):70.

[42] Xue J, Ge P, Wu Y. The prognosis and clinicopathological significance of histone deacetylase in hepatocellular carcinoma: a meta-analysis. Clin Exp Med. 2023;23(5):1515-1536.

[43] Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 2015;21(6):805-821.

[44] Trefely S, Lovell CD, Snyder NW, Wellen KE. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol Metab. 2020;38:100941.

[45] Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer. 2023;23(3):156-172.

[46] Zaidi N, Swinnen JV, Smans K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res. 2012;72(15):3709-37014.

[47] Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev. 2006;20(11):1394-1404.

[48] Wen J, Min X, Shen M, et al. ACLY facilitates colon cancer cell metastasis by CTNNB1. J Exp Clin Cancer Res. 2019;38(1):401.

[49] Lee JV, Berry CT, Kim K, et al. Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca2⁺-NFAT signaling. Genes Dev. 2018;32(7-8):497-511.

[50] Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM. Regulation of acetyl-CoA carboxylase. Biochem Soc Trans. 2006;34(pt 2):223-227.

[51] Rios Garcia M, Steinbauer B, Srivastava K, et al. Acetyl-CoA carboxylase 1-dependent protein acetylation controls breast cancer metastasis and recurrence. Cell Metab. 2017;26(6):842-855.e5.

[52] Chai P, Lan P, Li S, et al. Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA. Mol Cell. 2022;82(21):4116-4130.e6.

[53] Wilson BG, Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011;11(7):481-492.

[54] Kumar R, Li DQ, Müller S, Knapp S. Epigenomic regulation of oncogenesis by chromatin remodeling. Oncogene. 2016;35(34):4423-4436.

[55] Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol. 2006;7(6):437-447.

[56] Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273-304.

[57] Mashtalir N, D'Avino AR, Michel BC, et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell. 2018;175(5):1272-1288.

[58] Pépin D, Vanderhyden BC, Picketts DJ, Murphy BD. ISWI chromatin remodeling in ovarian somatic and germ cells: revenge of the NURFs. Trends Endocrinol Metab. 2007;18(5):215-224.

[59] Boyer LA, Latek RR, Peterson CL. The SANT domain: a unique histone-tail-binding module? Nat Rev Mol Cell Biol. 2004;5(2):158-163.

[60] Denslow SA, Wade PA. The human Mi-2/NuRD complex and gene regulation. Oncogene. 2007;26(37):5433-5438.

[61] Morrison AJ, Shen X. Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes. Nat Rev Mol Cell Biol. 2009;10(6):373-384.

[62] Uno K, Takita J, Yokomori K, et al. Aberrations of the hSNF5/INI1 gene are restricted to malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors in pediatric solid tumors. Genes Chromosomes Cancer. 2002;34(1):33-41.

[63] Lehmann LC, Hewitt G, Aibara S, et al. Mechanistic insights into autoinhibition of the oncogenic chromatin remodeler ALC1. Mol Cell. 2017;68(5):847-859.e7.

[64] Yang Y, Zhao X, Li HX. MiR-221 and miR-222 simultaneously target ARID1A and enhance proliferation and invasion of cervical cancer cells. Eur Rev Med Pharmacol Sci. 2016;20(8):1509-1515.

[65] Shi Y, Gao S, Zheng Y, Yao M, Ruan F. LncRNA CASC15 functions as an unfavorable predictor of ovarian cancer prognosis and inhibits tumor progression through regulation of miR-221/ARID1A axis. Onco Targets Ther. 2019;12:8725-8736.

[66] Huang LY, Zhao J, Chen H, et al. SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis. Nat Commun. 2018;9(1):3569.

[67] Schalch T, Duda S, Sargent DF, Richmond TJ. X-ray structure of a tetranucleosome and its implications for the chromatin fibre. Nature. 2005;436(7047):138-141.

[68] Rowley MJ, Corces VG. Organizational principles of 3D genome architecture. Nat Rev Genet. 2018;19(12):789-800.

[69] Huang H, Zhu Q, Jussila A, et al. CTCF mediates dosage-and sequence-context-dependent transcriptional insulation by forming local chromatin domains. Nat Genet. 2021;53(7):1064-1074.

[70] Misteli T. The self-organizing genome: principles of genome architecture and function. Cell. 2020;183(1):28-45.

[71] Reddy KL, Feinberg AP. Higher order chromatin organization in cancer. Semin Cancer Biol. 2013;23(2):109-115.

[72] Akdemir KC, Le VT, Chandran S, et al. Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nat Genet. 2020;52(3):294-305.

[73] Dixon JR, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485(7398):376-380.

[74] Kentepozidou E, Aitken SJ, Feig C, et al. Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains. Genome Biol. 2020;21(1):5.

[75] Li Y, Haarhuis JHI, Sedeño Cacciatore Á, et al. The structural basis for cohesin-CTCF-anchored loops. Nature. 2020;578(7795):472-476.

[76] Sima J, Chakraborty A, Dileep V, et al. Identifying cis elements for spatiotemporal control of mammalian DNA replication. Cell. 2019;176(4):816-830.e18.

[77] Flavahan WA, Drier Y, Johnstone SE, et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature. 2019;575(7781):229-233.

[78] Flavahan WA, Drier Y, Liau BB, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016;529(7584):110-114.

[79] Batut PJ, Bing XY, Sisco Z, Raimundo J, Levo M, Levine MS. Genome organization controls transcriptional dynamics during development. Science. 2022;375(6580):566-570.

[80] Lund E, Oldenburg AR, Collas P. Enriched domain detector: a program for detection of wide genomic enrichment domains robust against local variations. Nucleic Acids Res. 2014;42(11):e92.

[81] Leemans C, van der Zwalm MCH, Brueckner L, et al. Promoter-intrinsic and local chromatin features determine gene repression in LADs. Cell. 2019;177(4):852-864.

[82] van Steensel B, Belmont AS. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell. 2017;169(5):780-791.

[83] Ghosh S, Liu B, Wang Y, Hao Q, Zhou Z. Lamin A is an endogenous SIRT6 activator and promotes SIRT6-mediated DNA repair. Cell Rep. 2015;13(7):1396-1406.

[84] Lee JE, Kim MY. Cancer epigenetics: past, present and future. Semin Cancer Biol. 2022;83:4-14.

[85] Ren B, Yang J, Wang C, et al. High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis. J Hematol Oncol. 2021;14(1):120.

[86] Ge T, Gu X, Jia R, et al. Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities. Cancer Commun. 2022;42(11):1049-1082.

[87] Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89-92.

[88] Lovén J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320-334.

[89] Madakashira BP, Sadler KC. DNA methylation, nuclear organization, and cancer. Front Genet. 2017;8:76.

[90] Hansen KD, Timp W, Bravo HC, et al. Increased methylation variation in epigenetic domains across cancer types. Nat Genet. 2011;43(8):768-775.

[91] Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet. 2021;37(11):1012-1027.

[92] Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 1989;83(2):155-158.

[93] Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042-2054.

[94] Sproul D, Kitchen RR, Nestor CE, et al. Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol. 2012;13(10):R84.

[95] Stirzaker C, Song JZ, Ng W, et al. Methyl-CpG-binding protein MBD2 plays a key role in maintenance and spread of DNA methylation at CpG islands and shores in cancer. Oncogene. 2017;36(10):1328-1338.

[96] Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A, Clarke AR. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat Genet. 2003;34(2):145-147.

[97] Guo H, Vuille JA, Wittner BS, et al. DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs. Cell. 2023;186(13):2765-2782.

[98] Yu J, Hua R, Zhang Y, Tao R, Wang Q, Ni Q. DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter. J Cell Biochem. 2020;121(1):142-151.

[99] Muhammad JS, Manzoor S, Cui ZG, Khoder G. DNA methylation-mediated overexpression of CXCL1 in Helicobacter pylori-induced gastric cancer: in silico- and in vitro-based identification of a potential biomarker for carcinogenesis. Int J Mol Sci. 2023;24(1):795.

[100] Wolf A, Agnihotri S, Munoz D, Guha A. Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme. Neurobiol Dis. 2011;44(1):84-91.

[101] Kim HW, Park JE, Baek M, et al. Matrix metalloproteinase-1 (MMP1) upregulation through promoter hypomethylation enhances tamoxifen resistance in breast cancer. Cancers. 2022;14(5):1232.

[102] Gkountela S, Castro-Giner F, Szczerba BM, et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell. 2019;176(1-2):98-112.

[103] Lopez-Serra P, Marcilla M, Villanueva A, et al. A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nat Commun. 2014;5:3608.

[104] Liu H, Song Y, Qiu H, et al. Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ. 2020;27(3):966-983.

[105] Mäki-Nevala S, Ukwattage S, Wirta EV, et al. Immunoprofiles and DNA methylation of inflammatory marker genes in ulcerative colitis-associated colorectal tumorigenesis. Biomolecules. 2021;11(10):1440.

[106] Jahangiri R, Mosaffa F, Emami Razavi A, Teimoori-Toolabi L, Jamialahmadi K. PAX2 promoter methylation and AIB1 overexpression promote tamoxifen resistance in breast carcinoma patients. J Oncol Pharm Pract. 2022;28(2):310-325.

[107] Verma A, Singh A, Singh MP, et al. EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis. Nat Commun. 2022;13(1):7344.

[108] Piunti A, Shilatifard A. Epigenetic balance of gene expression by Polycomb and COMPASS families. Science. 2016;352(6290):aad9780.

[109] Kang-Decker N, Tong C, Boussouar F, et al. Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency. Cancer Cell. 2004;5(2):177-189.

[110] Narita T, Ito S, Higashijima Y, et al. Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release. Mol Cell. 2021;81(10):2166-2182.e6.

[111] Hogg SJ, Motorna O, Cluse LA, et al. Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition. Mol Cell. 2021;81(10):2183-2200.e13.

[112] Mansour MR, Abraham BJ, Anders L, et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science. 2014;346(6215):1373-1377.

[113] Tsang FHC, Law CT, Tang TCC, et al. Aberrant super-enhancer landscape in human hepatocellular carcinoma. Hepatology. 2019;69(6):2502-2517.

[114] de Almeida Nagata DE, Chiang EY, Jhunjhunwala S, et al. Regulation of tumor-associated myeloid cell activity by CBP/EP300 bromodomain modulation of H3K27 acetylation. Cell Rep. 2019;27(1):269-281.e4.

[115] Szade K, Gulati GS, Chan CKF, et al. Where hematopoietic stem cells live: the bone marrow niche. Antioxid Redox Signal. 2018;29(2):191-204.

[116] Du L, Liu X, Ren Y, et al. Loss of SIRT4 promotes the self-renewal of breast cancer stem cells. Theranostics. 2020;10(21):9458-9476.

[117] Ma Y, Qi Y, Wang L, Zheng Z, Zhang Y, Zheng J. SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis. Free Radic Biol Med. 2019;134:458-467.

[118] Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci Adv. 2015;1(5):e1500447.

[119] Stern C. Boveri and the early days of genetics. Nature. 1950;166(4219):446.

[120] Lazzerini-Denchi E, Sfeir A. Stop pulling my strings—what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol. 2016;17(6):364-378.

[121] Li SKH, Martin A. Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol Med. 2016;22(4):274-289.

[122] Ogiwara H, Ui A, Otsuka A, et al. Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. Oncogene. 2011;30(18):2135-2146.

[123] Qi W, Wang R, Chen H, et al. BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51. J Cell Sci. 2015;128(2):317-330.

[124] Chen Y, Zhang H, Xu Z, et al. A PARP1-BRG1-SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites. Nucleic Acids Res. 2019;47(16):8563-8580.

[125] Brownlee PM, Meisenberg C, Downs JA. The SWI/SNF chromatin remodelling complex: its role in maintaining genome stability and preventing tumourigenesis. DNA Repair. 2015;32:127-133.

[126] Chabanon RM, Morel D, Postel-Vinay S. Exploiting epigenetic vulnerabilities in solid tumors: novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin Cancer Biol. 2020;61:180-198.

[127] Watanabe R, Ui A, Kanno SI, et al. SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability. Cancer Res. 2014;74(9):2465-2475.

[128] Zhao B, Lin J, Rong L, et al. ARID1A promotes genomic stability through protecting telomere cohesion. Nat Commun. 2019;10(1):4067.

[129] Kakarougkas A, Ismail A, Chambers AL, et al. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol Cell. 2014;55(5):723-732.

[130] Ahel D, Horejsí Z, Wiechens N, et al. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009;325(5945):1240-1243.

[131] Verma P, Zhou Y, Cao Z, et al. ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells. Nat Cell Biol. 2021;23(2):160-171.

[132] Hnisz D, Schuijers J, Li CH, Young RA. Regulation and dysregulation of chromosome structure in cancer. Ann Rev Cancer Biol. 2018;2(1):21-40.

[133] Hnisz D, Weintraub AS, Day DS, et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science. 2016;351(6280):1454-1458.

[134] Ooi WF, Nargund AM, Lim KJ, et al. Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma. Gut. 2020;69(6):1039-1052.

[135] Cho SW, Xu J, Sun R, et al. Promoter of lncRNA gene PVT1 is a tumor-suppressor DNA boundary element. Cell. 2018;173(6):1398-1412.e22.

[136] Rubio-Perez C, Tamborero D, Schroeder MP, et al. In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunities. Cancer Cell. 2015;27(3):382-396.

[137] Marshall AD, Bailey CG, Champ K, et al. CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic. Oncogene. 2017;36(29):4100-4110.

[138] Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, et al. IntOGen-mutations identifies cancer drivers across tumor types. Nat Methods. 2013;10(11):1081-1082.

[139] Damaschke NA, Gawdzik J, Avilla M, et al. CTCF loss mediates unique DNA hypermethylation landscapes in human cancers. Clin Epigenetics. 2020;12(1):80.

[140] Kemp CJ, Moore JM, Moser R, et al. CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer. Cell Rep. 2014;7(4):1020-1029.

[141] Uhlen M, Zhang C, Lee S, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352):eaan2507.

[142] Martin TD, Patel RS, Cook DR, et al. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science. 2021;373(6561):1327-1335.

[143] Oreskovic E, Wheeler EC, Mengwasser KE, et al. Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1. Proc Natl Acad Sci U S A. 2022;119(7):e2120540119.

[144] Gerstberger S, Jiang Q, Ganesh K. Metastasis. Cell. 2023;186(8):1564-1579.

[145] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.

[146] Padmanaban V, Krol I, Suhail Y, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019;573(7774):439-444.

[147] Avgustinova A, Benitah SA. The epigenetics of tumour initiation: cancer stem cells and their chromatin. Curr Opin Genet Dev. 2016;36:8-15.

[148] Makohon-Moore AP, Zhang M, Reiter JG, et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet. 2017;49(3):358-366.

[149] Chatterjee A, Rodger EJ, Eccles MR. Epigenetic drivers of tumourigenesis and cancer metastasis. Semin Cancer Biol. 2018;51:149-159.

[150] Graff JR, Herman JG, Lapidus RG, et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995;55(22):5195-5199.

[151] Kudo Y, Kitajima S, Ogawa I, et al. Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. Clin Cancer Res. 2004;10(16):5455-5463.

[152] Jensen K, Patel A, Hoperia V, Larin A, Bauer A, Vasko V. Dynamic changes in E-cadherin gene promoter methylation during metastatic progression in papillary thyroid cancer. Exp Ther Med. 2010;1(3):457-462.

[153] Papageorgis P, Lambert AW, Ozturk S, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70(3):968-978.

[154] Cardenas H, Vieth E, Lee J, et al. TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells. Epigenetics. 2014;9(11):1461-1472.

[155] Sun L, Kong Y, Cao M, et al. Decreased expression of acetyl-CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma. Cancer Sci. 2017;108(7):1338-1346.

[156] Liang Y, Pi H, Liao L, et al. Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy. Environ Pollut. 2021;273:116504.

[157] Horibata Y, Ando H, Itoh M, Sugimoto H. Enzymatic and transcriptional regulation of the cytoplasmic acetyl-CoA hydrolase ACOT12. J Lipid Res. 2013;54(8):2049-2059.

[158] Lu M, Zhu WW, Wang X, et al. ACOT12-dependent alteration of acetyl-CoA drives hepatocellular carcinoma metastasis by epigenetic induction of epithelial–mesenchymal transition. Cell Metab. 2019;29(4):886-900.e5.

[159] Zhou X, Zhou Y, Shao W, Hong L, Lu M, Zhu W. ACOT12-mediated acetyl-CoA hydrolysis suppresses intrahepatic cholangiocarcinoma metastasis by inhibiting epithelial–mesenchymal transition. J Cancer. 2022;13(6):1734-1744.

[160] Shen Y, Wei W, Zhou DX. Histone acetylation enzymes coordinate metabolism and gene expression. Trends Plant Sci. 2015;20(10):614-621.

[161] Haque ME, Jakaria M, Akther M, Cho DY, Kim IS, Choi DK. The GCN5: its biological functions and therapeutic potentials. Clin Sci. 2021;135(1):231-257.

[162] Wang X, Qin G, Liang X, et al. Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma. Nat Commun. 2020;11(1):1141.

[163] Liu J, Gu J, Feng Z, et al. Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells. J Transl Med. 2016;14:7.

[164] Cheng C, Yang J, Li SW, et al. HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell Death Dis. 2021;12(2):137.

[165] Tang X, Li G, Su F, et al. HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration. Nucleic Acids Res. 2020;48(6):2912-2923.

[166] Ding S, Gao Y, Lv D, et al. DNTTIP1 promotes nasopharyngeal carcinoma metastasis via recruiting HDAC1 to DUSP2 promoter and activating ERK signaling pathway. EBioMedicine. 2022;81:104100.

[167] Wen Y, Zhang X, Li X, et al. Histone deacetylase (HDAC) 11 inhibits matrix metalloproteinase (MMP) 3 expression to suppress colorectal cancer metastasis. J Cancer. 2022;13(6):1923-1932.

[168] Leslie PL, Chao YL, Tsai YH, et al. Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes. Nat Commun. 2019;10(1):4192.

[169] Ma H, Chang H, Yang W, Lu Y, Hu J, Jin S. A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma. Mol Cancer. 2020;19(1):4.

[170] Centore RC, Sandoval GJ, Soares LMM, Kadoch C, Chan HM. Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies. Trends Genet. 2020;36(12):936-950.

[171] Wang G, Fu Y, Yang X, et al. Brg-1 targeting of novel miR550a-5p/RNF43/Wnt signaling axis regulates colorectal cancer metastasis. Oncogene. 2016;35(5):651-661.

[172] Shang XY, Shi Y, He DD, et al. ARID1A deficiency weakens BRG1–RAD21 interaction that jeopardizes chromatin compactness and drives liver cancer cell metastasis. Cell Death Dis. 2021;12(11):990.

[173] Sun X, Wang SC, Wei Y, et al. Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell. 2017;32(5):574-589.

[174] Jiang H, Cao HJ, Ma N, et al. Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis. Proc Natl Acad Sci U S A. 2020;117(9):4770-4780.

[175] Wang L, Zhao Z, Meyer MB, et al. CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell. 2014;25(1):21-36.

[176] Gomes AP, Ilter D, Low V, et al. Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization. Cancer Cell. 2019;36(4):402-417.e13.

[177] Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature. 2002;419(6907):641-645.

[178] Cai S, Lee CC, Kohwi-Shigematsu T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet. 2006;38(11):1278-1288.

[179] Qi H, Fu X, Li Y, et al. SATB1 promotes epithelial–mesenchymal transition and metastasis in prostate cancer. Oncol Lett. 2017;13(4):2577-2582.

[180] Wu D, Zeng L, Liu F, et al. Special AT-rich DNA-binding protein-1 expression is associated with liver cancer metastasis. Oncol Lett. 2016;12(6):4377-4384.

[181] Wan F, Cheng C, Wang Z, et al. SATB1 overexpression regulates the development and progression in bladder cancer through EMT. PLoS One. 2015;10(2):e0117518.

[182] Mir R, Pradhan SJ, Patil P, Mulherkar R, Galande S. Wnt/β-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression. Oncogene. 2016;35(13):1679-1691.

[183] Li QQ, Chen ZQ, Cao XX, et al. Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial–mesenchymal transition of breast cancer cells. Cell Death Differ. 2011;18(1):16-25.

[184] Eberhard J, Gaber A, Wangefjord S, et al. A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer. Br J Cancer. 2012;106(5):931-938.

[185] Kucuksayan H, Ozes ON, Akca H. Downregulation of SATB2 is critical for induction of epithelial-to-mesenchymal transition and invasion of NSCLC cells. Lung Cancer. 2016;98:122-129.

[186] Mansour MA, Hyodo T, Akter KA, et al. SATB1 and SATB2 play opposing roles in c-Myc expression and progression of colorectal cancer. Oncotarget. 2016;7(4):4993-5006.

[187] Kumari R, Deshmukh RS, Das S. Caspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis. Nat Commun. 2019;10(1):4255.

[188] Liu X, Wang X, Zhang J, et al. Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis. Oncogene. 2010;29(3):442-450.

[189] Chen M, Zhang J, Li N, et al. Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer. PLoS One. 2011;6(10):e25564.

[190] Dong C, Yuan T, Wu Y, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013;23(3):316-331.

[191] Li H, Wang J, Xu H, et al. Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells. Mol Cancer. 2013;12(1):110.

[192] Pulikkottil AJ, Bamezai S, Ammer T, et al. TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways. Leukemia. 2022;36(2):416-425.

[193] Vanharanta S, Shu W, Brenet F, et al. Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat Med. 2013;19(1):50-56.

[194] García JM, Silva J, Peña C, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer. 2004;41(2):117-124.

[195] Esteller M, Avizienyte E, Corn PG, et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz–Jeghers syndrome. Oncogene. 2000;19(1):164-168.

[196] Xiao C, Kim HS, Lahusen T, et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J Biol Chem. 2010;285(47):36776-36784.

[197] Zhong L, D'Urso A, Toiber D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140(2):280-293.

[198] Sebastián C, Zwaans BMM, Silberman DM, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151(6):1185-1199.

[199] Liu PY, Xu N, Malyukova A, et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ. 2013;20(3):503-514.

[200] Gu Z, Liu Y, Cai F, et al. Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation. Cancer Discov. 2019;9(9):1228-1247.

[201] Alam H, Tang M, Maitituoheti M, et al. KMT2D deficiency impairs super-enhancers to confer a glycolytic vulnerability in lung cancer. Cancer Cell. 2020;37(4):599-617.

[202] Maitituoheti M, Keung EZ, Tang M, et al. Enhancer reprogramming confers dependence on glycolysis and IGF signaling in KMT2D mutant melanoma. Cell Rep. 2020;33(3):108293.

[203] Koutsioumpa M, Hatziapostolou M, Polytarchou C, et al. Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming. Gut. 2019;68(7):1271-1286.

[204] Ding J, Li T, Wang X, et al. The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab. 2013;18(6):896-907.

[205] Zhao E, Ding J, Xia Y, et al. KDM4C and ATF4 cooperate in transcriptional control of amino acid metabolism. Cell Rep. 2016;14(3):506-519.

[206] Zhang H, Tang K, Ma J, et al. Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development. Nat Cell Biol. 2020;22(1):18-25.

[207] Lu Y, Zhou X, Zhao W, et al. Epigenetic inactivation of acetyl-CoA acetyltransferase 1 promotes the proliferation and metastasis in nasopharyngeal carcinoma by blocking ketogenesis. Front Oncol. 2021;11:667673.

[208] Koronowski KB, Greco CM, Huang H, et al. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation. Cell Rep. 2021;36(5):109487.

[209] Wu S, Fukumoto T, Lin J, et al. Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma. Nat Cancer. 2021;2(2):189-200.

[210] Ogiwara H, Takahashi K, Sasaki M, et al. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers. Cancer Cell. 2019;35(2):177-190.

[211] Lissanu Deribe Y, Sun Y, Terranova C, et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat Med. 2018;24(7):1047-1057.

[212] Wu Q, Madany P, Dobson JR, et al. The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation. Oncotarget. 2016;7(25):38270-38281.

[213] Nora EP, Goloborodko A, Valton AL, et al. Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization. Cell. 2017;169(5):930-944.e22.

[214] Turcan S, Makarov V, Taranda J, et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat Genet. 2018;50(1):62-72.

[215] Rao SSP, Huang SC, Glenn St Hilaire B, et al. Cohesin loss eliminates all loop domains. Cell. 2017;171(2):305-320.e24.

[216] de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374-403.

[217] Abou Khouzam R, Goutham HV, Zaarour RF, et al. Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy. Semin Cancer Biol. 2020;65:140-154.

[218] Li X, Gulati M, Larson AC, et al. Immune checkpoint blockade in pancreatic cancer: trudging through the immune desert. Semin Cancer Biol. 2022;86(pt 2):14-27.

[219] Vizoso M, Puig M, Carmona FJ, et al. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts. Carcinogenesis. 2015;36(12):1453-1463.

[220] Jiang L, Gonda TA, Gamble MV, et al. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res. 2008;68(23):9900-9908.

[221] Al-Kharashi LA, Al-Mohanna FH, Tulbah A, Aboussekhra A. The DNA methyl-transferase protein DNMT1 enhances tumor-promoting properties of breast stromal fibroblasts. Oncotarget. 2018;9(2):2329-2343.

[222] Mishra R, Haldar S, Placencio V, et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018;128(10):4472-4484.

[223] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162-174.

[224] Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179(2):977-983.

[225] Rodríguez-Ubreva J, Català-Moll F, Obermajer N, et al. Prostaglandin E2 leads to the acquisition of DNMT3A-dependent tolerogenic functions in human myeloid-derived suppressor cells. Cell Rep. 2017;21(1):154-167.

[226] Sido JM, Yang X, Nagarkatti PS, Nagarkatti M. Δ9-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid-derived suppressor cell activation via STAT3/S100A8. J Leukoc Biol. 2015;97(4):677-688.

[227] Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527(7577):249-253.

[228] Moufarrij S, Srivastava A, Gomez S, et al. Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer. Sci Rep. 2020;10(1):3470.

[229] He R, Feng X, Yang K, Zhou X, Li W, Zeng J. Construction of a 5-methylcytosine-related molecular signature to inform the prognosis and immunotherapy of lung squamous cell carcinoma. Expert Rev Mol Diagn. 2022;22(9):905-913.

[230] Collignon E, Canale A, Al Wardi C, et al. Immunity drives TET1 regulation in cancer through NF-κB. Sci Adv. 2018;4(6):eaap7309.

[231] Li A, Chen P, Leng Y, Kang J. Histone deacetylase 6 regulates the immunosuppressive properties of cancer-associated fibroblasts in breast cancer through the STAT3-COX2-dependent pathway. Oncogene. 2018;37(45):5952-5966.

[232] Kim DJ, Dunleavey JM, Xiao L, et al. Suppression of TGFβ-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition. Br J Cancer. 2018;118(10):1359-1368.

[233] Mormino A, Cocozza G, Fontemaggi G, et al. Histone-deacetylase 8 drives the immune response and the growth of glioma. Glia. 2021;69(11):2682-2698.

[234] Demoulin SA, Somja J, Duray A, et al. Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion. Oncoimmunology. 2015;4(6):e1008334.

[235] Ippolito L, Comito G, Parri M, et al. Lactate rewires lipid metabolism and sustains a metabolic–epigenetic axis in prostate cancer. Cancer Res. 2022;82(7):1267-1282.

[236] Zhang B, Li Y, Wu Q, et al. Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer. Nat Commun. 2021;12(1):1714.

[237] Giannoni E, Bianchini F, Masieri L, et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial–mesenchymal transition and cancer stemness. Cancer Res. 2010;70(17):6945-6956.

[238] Zhao D, Cai L, Lu X, et al. Chromatin regulator CHD1 remodels the immunosuppressive tumor microenvironment in PTEN-deficient prostate cancer. Cancer Discov. 2020;10(9):1374-1387.

[239] Mathur R, Alver BH, San Roman AK, et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet. 2017;49(2):296-302.

[240] Shen J, Ju Z, Zhao W, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24(5):556-562.

[241] Fukumoto T, Lin J, Fatkhutdinov N, et al. ARID2 deficiency correlates with the response to immune checkpoint blockade in melanoma. J Invest Dermatol. 2021;141(6):1564-1572.

[242] Zhou Y, Nan P, Li C, et al. Upregulation of MTA1 in colon cancer drives a CD8+ T cell-rich but classical macrophage-lacking immunosuppressive tumor microenvironment. Front Oncol. 2022;12:825783.

[243] Davalos V, Esteller M. Cancer epigenetics in clinical practice. CA Cancer J Clin. 2023;73(4):376-424.

[244] Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531.

[245] Jang HJ, Hostetter G, Macfarlane AW, et al. A phase II trial of guadecitabine plus atezolizumab in metastatic urothelial carcinoma progressing after initial immune checkpoint inhibitor therapy. Clin Cancer Res. 2023;29(11):2052-2065.

[246] Topper MJ, Vaz M, Marrone KA, Brahmer JR, Baylin SB. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol. 2020;17(2):75-90.

[247] Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181-185.

[248] Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442.

[249] Honma D, Kanno O, Watanabe J, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017;108(10):2069-2078.

[250] Izutsu K, Makita S, Nosaka K, et al. An open-label, single-arm phase 2 trial of valemetostat for relapsed or refractory adult T-cell leukemia/lymphoma. Blood. 2023;141(10):1159-1168.

[251] Okada Y, Feng Q, Lin Y, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121(2):167-178.

[252] Lonetti A, Indio V, Laginestra MA, et al. Inhibition of methyltransferase DOT1L sensitizes to sorafenib treatment AML cells irrespective of MLL-rearrangements: a novel therapeutic strategy for pediatric AML. Cancers. 2020;12(7):1972.

[253] Shen DD, Pang JR, Bi YP, et al. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer. Mol Cancer. 2022;21(1):75.

[254] Fang Y, Liao G, Yu B. LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol. 2019;12(1):129.

[255] Hollebecque A, Salvagni S, Plummer R, et al. Phase I study of lysine-specific demethylase 1 inhibitor, CC-90011, in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma. Clin Cancer Res. 2021;27(2):438-446.

[256] Perillo B, Tramontano A, Pezone A, Migliaccio A. LSD1: more than demethylation of histone lysine residues. Exp Mol Med. 2020;52(12):1936-1947.

[257] Wang J, Hevi S, Kurash JK, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet. 2009;41(1):125-129.

[258] Xu S, Wang X, Yang Y, Li Y, Wu S. LSD1 silencing contributes to enhanced efficacy of anti-CD47/PD-L1 immunotherapy in cervical cancer. Cell Death Dis. 2021;12(4):282.

[259] Qin Y, Vasilatos SN, Chen L, et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene. 2019;38(3):390-405.

[260] Park JW, Han JW. Targeting epigenetics for cancer therapy. Arch Pharm Res. 2019;42(2):159-170.

[261] Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 2007;12(10):1247-1252.

[262] Terranova-Barberio M, Thomas S, Ali N, et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 2017;8(69):114156-114172.

[263] Thomas S, Thurn KT, Biçaku E, Marchion DC, Münster PN. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat. 2011;130(2):437-447.

[264] O'Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-2499.

[265] Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598-607.

[266] Connolly RM, Li H, Jankowitz RC, et al. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a phase II National Cancer Institute/stand up to cancer study. Clin Cancer Res. 2017;23(11):2691-2701.

[267] Faivre EJ, McDaniel KF, Albert DH, et al. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature. 2020;578(7794):306-310.

[268] Feng M, Xu H, Zhou W, Pan Y. The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma. J Exp Clin Cancer Res. 2023;42(1):44.

[269] Pang Y, Bai G, Zhao J, et al. The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer. J Transl Med. 2022;20(1):336.

[270] Stuhlmiller TJ, Miller SM, Zawistowski JS, et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains. Cell Rep. 2015;11(3):390-404.

[271] Leonard B, Brand TM, O'Keefe RA, et al. BET inhibition overcomes receptor tyrosine kinase-mediated cetuximab resistance in HNSCC. Cancer Res. 2018;78(15):4331-4343.

[272] Sun C, Yin J, Fang Y, et al. BRD4 inhibition is synthetic lethal with PARP inhibitors through the induction of homologous recombination deficiency. Cancer Cell. 2018;33(3):401-416.

[273] Fiorentino FP, Marchesi I, Schröder C, Schmidt R, Yokota J, Bagella L. BET-inhibitor I-BET762 and PARP-inhibitor talazoparib synergy in small cell lung cancer cells. Int J Mol Sci. 2020;21(24):9595.

[274] Yang L, Zhang Y, Shan W, et al. Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med. 2017;9(400):eaal1645.

[275] Karakashev S, Zhu H, Yokoyama Y, et al. BET bromodomain inhibition synergizes with PARP inhibitor in epithelial ovarian cancer. Cell Rep. 2017;21(12):3398-3405.

[276] Maegawa S, Gough SM, Watanabe-Okochi N, et al. Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res. 2014;24(4):580-591.

[277] Timp W, Bravo HC, McDonald OG, et al. Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors. Genome Med. 2014;6(8):61.

[278] Zheng H, Xie W. The role of 3D genome organization in development and cell differentiation. Nat Rev Mol Cell Biol. 2019;20(9):535-550.

[279] Feng Y, Liu X, Pauklin S. 3D chromatin architecture and epigenetic regulation in cancer stem cells. Protein Cell. 2021;12(6):440-454.

[280] Casado-Pelaez M, Bueno-Costa A, Esteller M. Single cell cancer epigenetics. Trends Cancer. 2022;8(10):820-838.

[281] Mehrmohamadi M, Sepehri MH, Nazer N, Norouzi MR. A comparative overview of epigenomic profiling methods. Front Cell Dev Biol. 2021;9:714687.

[282] Philpott M, Watson J, Thakurta A, et al. Nanopore sequencing of single-cell transcriptomes with scCOLOR-seq. Nat Biotechnol. 2021;39(12):1517-1520.

[283] Johannessen LE, Brandal P, Myklebust TÅ, Heim S, Micci F, Panagopoulos I. MGMT gene promoter methylation status—assessment of two pyrosequencing kits and three methylation-specific PCR methods for their predictive capacity in glioblastomas. Cancer Genomics Proteomics. 2018;15(6):437-446.

[284] Locke WJ, Guanzon D, Ma C, et al. DNA methylation cancer biomarkers: translation to the clinic. Front Genet. 2019;10:1150.

[285] Malta TM, de Souza CF, Sabedot TS, et al. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro Oncol. 2018;20(5):608-620.

[286] Bond DR, Uddipto K, Enjeti AK, Lee HJ. Single-cell epigenomics in cancer: charting a course to clinical impact. Epigenomics. 2020;12(13):1139-1151.

RIGHTS & PERMISSIONS

2024 2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.