The role of H3K27me3 methylation in cancer development

Abstract

Although the importance of histone methylation in epigenetics was first suggested more than 50 years ago, research into histone modifications conducted in the past decade has led to an exponential increase in our understanding of histone H3 modifications. In particular, the involvement of H3 histone 27 lysine trimethylation in the development of various cancer phenotypes has been demonstrated. Unlike mutations in the DNA sequence, such epigenetic changes are reversible, suggesting that inhibitors of H3 histone 27 amino acid methylation enzymes could be used as anti-cancer agents. Here, we outline the regulatory functions of H3 histone 27 lysine trimethylation carried out by different enzymes, in carcinogenesis. We describe the role of H3 histone 27 lysine trimethylation as an important epigenetic regulatory mechanism in the development of various cancers via effects on inflammation, DNA damage repair, cell proliferation, cell metastasis, regulatory cell death, ferroptosis, and angiogenesis. Finally, we focus specifically on H3 histone 27 lysine trimethylation regulators and their future development as anti-cancer drugs.

Keywords

Cancer / Cancer therapy / DNA damage repair / Epigenetic regulators / H3K27me3 / Histone methylation

References

[] Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature, 2007, 449(7163): 731-734.

[] Agmon E, Solon J, Bassereau P, Stockwell BR. Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Scientific Reports, 2018, 8(1): 5155.

[] Ahmad F, Patrick S, Sheikh T, Sharma V, Pathak P, Malgulwar PB, Kumar A, Joshi SD, Sarkar C, Sen E. Telomerase reverse transcriptase (TERT)—Enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma. Journal of Neurochemistry, 2017, 143(6): 671-683.

[] Akpa CA, Kleo K, Lenze D, Oker E, Dimitrova L, Hummel M. DZNep-mediated apoptosis in B-cell lymphoma is independent of the lymphoma type, EZH2 mutation status and MYC, BCL2 or BCL6 translocations. PLoS ONE, 2019, 14(8).

[] Allen EA, Baehrecke EH. Autophagy in animal development. Cell Death and Differentiation, 2020, 27(3): 903-918.

[] Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proceedings of the National Academy of Sciences of the United States of America, 1964, 51(5): 786-794.

[] Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, DiPaola RS, Lotze MT, White E. Principles and current strategies for targeting autophagy for cancer treatment. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 2011, 17(4): 654-666.

[] Arango Duque G, Descoteaux A. Macrophage cytokines: Involvement in immunity and infectious diseases. Frontiers in Immunology, 2014, 5: 491.

[] Bai B, Liu Y, Fu XM, Qin HY, Li GK, Wang HC, Sun SL. Dysregulation of EZH2/miR-138-5p axis contributes to radiosensitivity in hepatocellular carcinoma cell by downregulating hypoxia-inducible factor 1 alpha (HIF-1α). Oxidative Medicine and Cellular Longevity, 2022, 2022: 7608712.

[] Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell, 2007, 129(4): 823-837.

[] Bedford MT, Clarke SG. Protein arginine methylation in mammals: Who, what, and why. Molecular Cell, 2009, 33(1): 1-13.

[] Benard A, Janssen CM, van den Elsen PJ, van Eggermond MC, Hoon DS, van de Velde CJ, Kuppen PJ. Chromatin status of apoptosis genes correlates with sensitivity to chemo-, immune- and radiation therapy in colorectal cancer cell lines. Apoptosis : An International Journal on Programmed Cell Death, 2014, 19(12): 1769-1778.

[] Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, Zapatka M, Northcott PA, Sturm D, Wang W, Radlwimmer B, Højfeldt JW, Truffaux N, Castel D, Schubert S, Ryzhova M, Seker-Cin H, Gronych J, Johann PD, Stark S, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell, 2013, 24(5): 660-672.

[] Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nature Reviews Cancer, 2003, 3(6): 401-410.

[] Blouw B, Song H, Tihan T, Bosze J, Ferrara N, Gerber HP, Johnson RS, Bergers G. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell, 2003, 4(2): 133-146.

[] Bluff JE, Menakuru SR, Cross SS, Higham SE, Balasubramanian SP, Brown NJ, Reed MW, Staton CA. Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. British Journal of Cancer, 2009, 101(4): 666-672.

[] Bossi P, Viale G, Lee AK, Alfano R, Coggi G, Bosari S. Angiogenesis in colorectal tumors: Microvessel quantitation in adenomas and carcinomas with clinicopathological correlations. Cancer Research, 1995, 55(21): 5049-5053.

[] Boya P, Codogno P, Rodriguez-Muela N. Autophagy in stem cells: Repair, remodelling and metabolic reprogramming. Development (Cambridge, England), 2018, 145(4).

[] Byvoet P, Shepherd GR, Hardin JM, Noland BJ. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Archives of Biochemistry and Biophysics, 1972, 148(2): 558-567.

[] Cacabelos R, Torrellas C, Carrera I, Cacabelos P, Corzo L, Fernández-Novoa L, Tellado I, Carril JC, Aliev G. Novel therapeutic strategies for dementia. CNS & Neurological Disorders Drug Targets, 2016, 15(2): 141-241.

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

[] Chen X, He Y, Lu F. Autophagy in stem cell biology: A perspective on stem cell self-renewal and differentiation. Stem Cells International, 2018, 2018: 9131397.

[] Chen Y, Li X, Xu J, Xiao H, Tang C, Liang W, Zhu X, Fang Y, Wang H, Shi J. Knockdown of nuclear receptor binding SET domain-containing protein 1 (NSD1) inhibits proliferation and facilitates apoptosis in paclitaxel-resistant breast cancer cells via inactivating the Wnt/β-catenin signaling pathway. Bioengineered, 2022, 13(2): 3526-3536.

[] Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: Serendipity and chemical biology. Chemistry & Biology, 2013, 20(5): 648-659.

[] Chu X, Zhong L, Yu L, Xiong L, Li J, Dan W, Ye J, Liu C, Luo X, Liu B. GSK-J4 induces cell cycle arrest and apoptosis via ER stress and the synergism between GSK-J4 and decitabine in acute myeloid leukemia KG-1a cells. Cancer Cell International, 2020, 20: 209.

[] Chung C, Sweha SR, Pratt D, Tamrazi B, Panwalkar P, Banda A, Bayliss J, Hawes D, Yang F, Lee HJ, Shan M, Cieslik M, Qin T, Werner CK, Wahl DR, Lyssiotis CA, Bian Z, Shotwell JB, Yadav VN, Koschmann C, et al. Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas. Cancer Cell, 2020, 38(3): 334-3499.

[] Clarke AJ, Simon AK. Autophagy in the renewal, differentiation and homeostasis of immune cells. Nature Reviews Immunology, 2019, 19(3): 170-183.

[] Cuervo AM. Autophagy: In sickness and in health. Trends in Cell Biology, 2004, 14(2): 70-77.

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

[] De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell, 2007, 130(6): 1083-1094.

[] Deb G, Singh AK, Gupta S. EZH2: Not EZHY (easy) to deal. Molecular Cancer Research MCR, 2014, 12(5): 639-653.

[] Deretic V. Autophagy in inflammation, infection, and immunometabolism. Immunity, 2021, 54(3): 437-453.

[] Dev A, Sardoiwala MN, Kushwaha AC, Karmakar S, Choudhury SR. Genistein nanoformulation promotes selective apoptosis in oral squamous cell carcinoma through repression of 3PK-EZH2 signalling pathway. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 2021, 80.

[] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd Stockwell BR. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.

[] Dong S, Wang Q, Kao YR, Diaz A, Tasset I, Kaushik S, Thiruthuvanathan V, Zintiridou A, Nieves E, Dzieciatkowska M, Reisz JA, Gavathiotis E, D'Alessandro A, Will B, Cuervo AM. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature, 2021, 591(7848): 117-123.

[] El-Deiry WS. Regulation of p53 downstream genes. Seminars in Cancer Biology, 1998, 8(5): 345-357.

[] Espinosa E, Zamora P, Feliu J, González Barón M. Classification of anticancer drugs—A new system based on therapeutic targets. Cancer Treatment Reviews, 2003, 29(6): 515-523.

[] Ezponda T, Licht JD. Molecular pathways: Deregulation of histone h3 lysine 27 methylation in cancer-different paths, same destination. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 2014, 20(19): 5001-5008.

[] Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, et al. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Seminars in Cancer Biology, 2015, 35(Suppl): S25-S54.

[] Ferrari KJ, Scelfo A, Jammula S, Cuomo A, Barozzi I, Stützer A, Fischle W, Bonaldi T, Pasini D. Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Molecular Cell, 2014, 53(1): 49-62.

[] Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. The American Journal of Pathology, 1997, 151(3): 679-688.

[] Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, et al. Molecular definitions of autophagy and related processes. The EMBO Journal, 2017, 36(13): 1811-1836.

[] Galluzzi L, Green DR. Autophagy-independent functions of the autophagy machinery. Cell, 2019, 177(7): 1682-1699.

[] Gao SB, Li KL, Qiu H, Zhu LY, Pan CB, Zhao Y, Wei SH, Shi S, Jin GH, Xue LX. Enhancing chemotherapy sensitivity by targeting PcG via the ATM/p53 pathway. American Journal of Cancer Research, 2017, 7(9): 1874-1883.

[] Gao S, Xiong J, Zhang C, Berquist BR, Yang R, Zhao M, Molascon AJ, Kwiatkowski SY, Yuan D, Qin Z, Wen J, Kapler GM, Andrews PC, Miao W, Liu Y. Impaired replication elongation in Tetrahymena mutants deficient in histone H3 Lys 27 monomethylation. Genes & Development, 2013, 27(15): 1662-1679.

[] Gardner EE, Lok BH, Schneeberger VE, Desmeules P, Miles LA, Arnold PK, Ni A, Khodos I, de Stanchina E, Nguyen T, Sage J, Campbell JE, Ribich S, Rekhtman N, Dowlati A, Massion PP, Rudin CM, Poirier JT. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 axis. Cancer Cell, 2017, 31(2): 286-299.

[] Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. The Journal of Pathology, 2010, 221(1): 3-12.

[] Gu X, Xu T, He Y. A histone H3 lysine-27 methyltransferase complex represses lateral root formation in Arabidopsis thaliana. Molecular Plant, 2014, 7(6): 977-988.

[] Hahn MA, Hahn T, Lee DH, Esworthy RS, Kim BW, Riggs AD, Chu FF, Pfeifer GP. Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. Cancer Research, 2008, 68(24): 10280-10289.

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

[] Hansen TE, Johansen T. Following autophagy step by step. BMC Biology, 2011, 9: 39.

[] Harper JW, Elledge SJ. The DNA damage response: Ten years after. Molecular Cell, 2007, 28(5): 739-745.

[] Heintzman ND, Hon GC, Hawkins RD, Kheradpour P, Stark A, Harp LF, Ye Z, Lee LK, Stuart RK, Ching CW, Ching KA, Antosiewicz-Bourget JE, Liu H, Zhang X, Green RD, Lobanenkov VV, Stewart R, Thomson JA, Crawford GE, Kellis M, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature, 2009, 459(7243): 108-112.

[] Hou C, Xiao L, Ren X, Cheng L, Guo B, Zhang M, Yan N. EZH2-mediated H3K27me3 is a predictive biomarker and therapeutic target in uveal melanoma. Frontiers in Genetics, 2022, 13: 1013475.

[] Huang C, Xiang Y, Wang Y, Li X, Xu L, Zhu Z, Zhang T, Zhu Q, Zhang K, Jing N, Chen CD. Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell Research, 2010, 20(2): 154-165.

[] Huang JP, Ling K. EZH2 and histone deacetylase inhibitors induce apoptosis in triple negative breast cancer cells by differentially increasing H3 Lys²⁷ acetylation in the BIM gene promoter and enhancers. Oncology Letters, 2017, 14(5): 5735-5742.

[] Huang Y, Yu SH, Zhen WX, Cheng T, Wang D, Lin JB, Wu YH, Wang YF, Chen Y, Shu LP, Wang Y, Sun XJ, Zhou Y, Yang F, Hsu CH, Xu PF. Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2. Theranostics, 2021, 11(14): 6891-6904.

[] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. The New England Journal of Medicine, 2004, 350(23): 2335-2342.

[] Imgruet MK, Lutze J, An N, Hu B, Khan S, Kurkewich J, Martinez TC, Wolfgeher D, Gurbuxani SK, Kron SJ, McNerney ME. Loss of a 7q gene, CUX1, disrupts epigenetically driven DNA repair and drives therapy-related myeloid neoplasms. Blood, 2021, 138(9): 790-805.

[] Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature, 2009, 461(7267): 1071-1078.

[] Jacob Y, Feng S, LeBlanc CA, Bernatavichute YV, Stroud H, Cokus S, Johnson LM, Pellegrini M, Jacobsen SE, Michaels SD. ATXR5 and ATXR6 are H3K27 monomethyltransferases required for chromatin structure and gene silencing. Nature Structural & Molecular Biology, 2009, 16(7): 763-768.

[] Jain P, Ballare C, Blanco E, Vizan P, Di Croce L. PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells. eLife, 2020, 9.

[] Jedinak A, Dudhgaonkar S, Sliva D. Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology, 2010, 215(3): 242-249.

[] Jiang W, Chen L, Zheng S. Global reprogramming of apoptosis-related genes during brain development. Cells, 2021, 10(11): 2901.

[] Jubb AM, Cesario A, Ferguson M, Congedo MT, Gatter KC, Lococo F, Mulè A, Pezzella F. Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. British Journal of Cancer, 2011, 104(12): 1877-1881.

[] Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death and Differentiation, 2018, 25(1): 65-80.

[] Kalkavan H, Green DR. MOMP, cell suicide as a BCL-2 family business. Cell Death and Differentiation, 2018, 25(1): 46-55.

[] Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nature Reviews Molecular Cell Biology, 2018, 19(6): 365-381.

[] Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, Nalin C, Kufe D. Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94(13): 6939-6942.

[] Kim J, Yu J. Interrogating genomic and epigenomic data to understand prostate cancer. Biochimica Et Biophysica Acta, 2012, 1825(2): 186-196.

[] Klionsky DJ. Autophagy: From phenomenology to molecular understanding in less than a decade. Nature Reviews Molecular Cell Biology, 2007, 8(11): 931-937.

[] Kornberg RD. Chromatin structure: A repeating unit of histones and DNA. Science (New York, NY), 1974, 184(4139): 868-871.

[] Kouzarides T. Chromatin modifications and their function. Cell, 2007, 128(4): 693-705.

[] Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H, Eberhard D, Hutchinson S, Jones E, Katso R, Leveridge M, Mander PK, Mosley J, Ramirez-Molina C, Rowland P, Schofield CJ, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature, 2012, 488(7411): 404-408.

[] Kusakabe Y, Chiba T, Oshima M, Koide S, Rizq O, Aoyama K, Ao J, Kaneko T, Kanzaki H, Kanayama K, Maeda T, Saito T, Nakagawa R, Kobayashi K, Kiyono S, Nakamura M, Ogasawara S, Suzuki E, Nakamoto S, Yasui S, et al. EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma. Scientific Reports, 2021, 11(1): 21396.

[] Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature, 2007, 449(7163): 689-694.

[] Lavrik I, Golks A, Krammer PH. Death receptor signaling. Journal of Cell Science, 2005, 118(Pt 2): 265-267.

[] Lee M, Nam HY, Kang HB, Lee WH, Lee GH, Sung GJ, Han MW, Cho KJ, Chang EJ, Choi KC, Kim SW, Kim SY. Epigenetic regulation of p62/SQSTM1 overcomes the radioresistance of head and neck cancer cells via autophagy-dependent senescence induction. Cell Death & Disease, 2021, 12(3): 250.

[] Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science (New York, NY), 2007, 318(5849): 447-450.

[] Levine B. Cell biology: Autophagy and cancer. Nature, 2007, 446(7137): 745-747.

[] Levine B, Klionsky DJ. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Developmental Cell, 2004, 6(4): 463-477.

[] Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell, 2008, 132(1): 27-42.

[] Levine B, Kroemer G. Biological functions of autophagy genes: A disease perspective. Cell, 2019, 176(1–2): 11-42.

[] Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science (New York, NY), 2013, 340(6134): 857-861.

[] Li H, Cai Q, Wu H, Vathipadiekal V, Dobbin ZC, Li T, Hua X, Landen CN, Birrer MJ, Sánchez-Beato M, Zhang R. SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK. Molecular Cancer Research: MCR, 2012, 10(11): 1462-1472.

[] Li H, Zhang R. Role of EZH2 in epithelial ovarian cancer: From biological insights to therapeutic target. Frontiers in Oncology, 2013, 3: 47.

[] Li J, Xi Y, Li W, McCarthy RL, Stratton SA, Zou W, Li W, Dent SY, Jain AK, Barton MC. TRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation. Oncogene, 2017, 36(21): 2991-3001.

[] Li XJ, Li QL, Ju LG, Zhao C, Zhao LS, Du JW, Wang Y, Zheng L, Song BL, Li LY, Li L, Wu M. Deficiency of histone methyltransferase SET domain-containing 2 in liver leads to abnormal lipid metabolism and HCC. Hepatology (Baltimore, MD), 2021, 73(5): 1797-1815.

[] Liang W, Wu J, Qiu X. LINC01116 facilitates colorectal cancer cell proliferation and angiogenesis through targeting EZH2-regulated TPM1. Journal of Translational Medicine, 2021, 19(1): 45.

[] Lin H, Guo Q, Lu S, Chen J, Li X, Gong M, Tang L, Wen J. LncRNA SUMO1P3 promotes proliferation and inhibits apoptosis in colorectal cancer by epigenetically silencing CPEB3. Biochemical and Biophysical Research Communications, 2019, 511(2): 239-245.

[] Lin H, Wang Y, Wang Y, Tian F, Pu P, Yu Y, Mao H, Yang Y, Wang P, Hu L, Lin Y, Liu Y, Xu Y, Chen CD. Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans. Cell Research, 2010, 20(8): 899-907.

[] Liu C, Fu H, Liu X, Lei Q, Zhang Y, She X, Liu Q, Liu Q, Sun Y, Li G, Wu M. LINC00470 coordinates the epigenetic regulation of ELFN2 to distract GBM cell autophagy. Molecular Therapy: THe Journal of the American Society of Gene Therapy, 2018, 26(9): 2267-2281.

[] Liu GZ, Xu XW, Tao SH, Gao MJ, Hou ZH. HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression. Journal of Biomedical Science, 2021, 28(1): 67.

[] Liu Y, Taverna SD, Muratore TL, Shabanowitz J, Hunt DF, Allis CD. RNAi-dependent H3K27 methylation is required for heterochromatin formation and DNA elimination in Tetrahymena. Genes & Development, 2007, 21(12): 1530-1545.

[] Lyu T, Jia N, Wang J, Yan X, Yu Y, Lu Z, Bast RC Jr Hua K, Feng W. Expression and epigenetic regulation of angiogenesis-related factors during dormancy and recurrent growth of ovarian carcinoma. Epigenetics, 2013, 8(12): 1330-1346.

[] Ma L, Lin K, Chang G, Chen Y, Yue C, Guo Q, Zhang S, Jia Z, Huang TT, Zhou A, Huang S. Aberrant activation of β-catenin signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2. Cancer Research, 2019, 79(1): 72-85.

[] Ma S, Xu L, Chen L, Sun X, Hu F, Gong Y, Yang R, Li J, Wang Q, Huang S, Zhou H, Wang J. Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury. Biochemical Pharmacology, 2022, 203.

[] Makarevich G, Leroy O, Akinci U, Schubert D, Clarenz O, Goodrich J, Grossniklaus U, Köhler C. Different Polycomb group complexes regulate common target genes in Arabidopsis. EMBO Reports, 2006, 7(9): 947-952.

[] Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nature Reviews Genetics, 2010, 11(4): 285-296.

[] Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nature Reviews Cancer, 2007, 7(12): 961-967.

[] Mejlvang J, Olsvik H, Svenning S, Bruun JA, Abudu YP, Larsen KB, Brech A, Hansen TE, Brenne H, Hansen T, Stenmark H, Johansen T. Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. The Journal of Cell Biology, 2018, 217(10): 3640-3655.

[] Mizushima N. Autophagy: Process and function. Genes & Development, 2007, 21(22): 2861-2873.

[] Mizushima N, Komatsu M. Autophagy: Renovation of cells and tissues. Cell, 2011, 147(4): 728-741.

[] Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nature Cell Biology, 2010, 12(9): 823-830.

[] Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annual Review of Cell and Developmental Biology, 2011, 27: 107-132.

[] Monsky WL, Mouta Carreira C, Tsuzuki Y, Gohongi T, Fukumura D, Jain RK. Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: Mammary fat pad versus cranial tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 2002, 8(4): 1008-1013.

[] Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, Magnuson T. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Current Biology: CB, 2005, 15(10): 942-947.

[] Morrissey C, True LD, Roudier MP, Coleman IM, Hawley S, Nelson PS, Coleman R, Wang YC, Corey E, Lange PH, Higano CS, Vessella RL. Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases. Clinical & Experimental Metastasis, 2008, 25(4): 377-388.

[] Mosammaparast N, Shi Y. Reversal of histone methylation: Biochemical and molecular mechanisms of histone demethylases. Annual Review of Biochemistry, 2010, 79: 155-179.

[] Mozzetta C, Pontis J, Ait-Si-Ali S. Functional crosstalk between lysine methyltransferases on histone substrates: The case of G9A/GLP and polycomb repressive complex 2. Antioxidants & Redox Signaling, 2015, 22(16): 1365-1381.

[] Mozzetta C, Pontis J, Fritsch L, Robin P, Portoso M, Proux C, Margueron R, Ait-Si-Ali S. The histone H3 lysine 9 methyltransferases G9a and GLP regulate polycomb repressive complex 2-mediated gene silencing. Molecular Cell, 2014, 53(2): 277-289.

[] Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Molecular Cell, 2001, 7(3): 683-694.

[] Nakka K, Hachmer S, Mokhtari Z, Kovac R, Bandukwala H, Bernard C, Li Y, Xie G, Liu C, Fallahi M, Megeney LA, Gondin J, Chazaud B, Brand M, Zha X, Ge K, Dilworth FJ. JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment. Science (New York, NY), 2022, 377(6606): 666-669.

[] Ning S, Ma X. Dephosphorylation-induced EZH2 activation mediated RECK downregulation by ERK1/2 signaling. Journal of Cellular Physiology, 2019, 234(10): 19010-19018.

[] Nitiss JL. DNA topoisomerase II and its growing repertoire of biological functions. Nature Reviews. Cancer, 2009, 9(5): 327-337.

[] Nowell PC. The clonal evolution of tumor cell populations. Science (New York, NY), 1976, 194(4260): 23-28.

[] Pang B, de Jong J, Qiao X, Wessels LF, Neefjes J. Chemical profiling of the genome with anti-cancer drugs defines target specificities. Nature Chemical Biology, 2015, 11(7): 472-480.

[] Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. The EMBO Journal, 2004, 23(20): 4061-4071.

[] Peralta-Arrieta I, Trejo-Villegas OA, Armas-López L, Ceja-Rangel HA, Ordóñez-Luna MDC, Pineda-Villegas P, González-López MA, Ortiz-Quintero B, Mendoza-Milla C, Zatarain-Barrón ZL, Arrieta O, Zúñiga J, Ávila-Moreno F. Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer. European Journal of Cancer (Oxford, England: 1990), 2022, 160: 189-205.

[] Polo SE, Jackson SP. Dynamics of DNA damage response proteins at DNA breaks: A focus on protein modifications. Genes & Development, 2011, 25(5): 409-433.

[] Ponpuak M, Mandell MA, Kimura T, Chauhan S, Cleyrat C, Deretic V. Secretory autophagy. Current Opinion in Cell Biology, 2015, 35: 106-116.

[] Porazzi P, Petruk S, Pagliaroli L, De Dominici M, Deming D 2nd Puccetti MV, Kushinsky S, Kumar G, Minieri V, Barbieri E, Deliard S, Grande A, Trizzino M, Gardini A, Canaani E, Palmisiano N, Porcu P, Ertel A, Fortina P, Eischen CM, et al. Targeting chemotherapy to decondensed H3K27me3-marked chromatin of AML cells enhances leukemia suppression. Cancer Research, 2022, 82(3): 458-471.

[] Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell, 2011, 146(6): 873-887.

[] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell, 2010, 141(1): 39-51.

[] Rabinowitz JD, White E. Autophagy and metabolism. Science (New York, NY), 2010, 330(6009): 1344-1348.

[] Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis: An International Journal on Programmed Cell Death, 2017, 22(7): 898-919.

[] Ricci B, Millner TO, Pomella N, Zhang X, Guglielmi L, Badodi S, Ceric D, Gemma C, Cognolato E, Zhang Y, Brandner S, Barnes MR, Marino S. Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma. Oncogene, 2020, 39(12): 2523-2538.

[] Rogov V, Dötsch V, Johansen T, Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Molecular Cell, 2014, 53(2): 167-178.

[] Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L. Microautophagy of cytosolic proteins by late endosomes. Developmental Cell, 2011, 20(1): 131-139.

[] Saraste A, Pulkki K. Morphologic and biochemical hallmarks of apoptosis. Cardiovascular Research, 2000, 45(3): 528-537.

[] Schubert D, Primavesi L, Bishopp A, Roberts G, Doonan J, Jenuwein T, Goodrich J. Silencing by plant polycomb-group genes requires dispersed trimethylation of histone H3 at lysine 27. The EMBO Journal, 2006, 25(19): 4638-4649.

[] Schuldt L, Reimann M, von Brandenstein K, Steinmetz J, Döding A, Schulze-Späte U, Jacobs C, Symmank J. Palmitate-triggered COX2/PGE2-related hyperinflammation in dual-stressed PdL fibroblasts is mediated by repressive H3K27 trimethylation. Cells, 2022, 11(6): 955.

[] Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis, 2010, 31(1): 27-36.

[] Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Molecular Cell, 2008, 32(4): 491-502.

[] Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004, 119(7): 941-953.

[] Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Molecular Cell, 2007, 25(1): 1-14.

[] Soria G, Polo SE, Almouzni G. Prime, repair, restore: The active role of chromatin in the DNA damage response. Molecular Cell, 2012, 46(6): 722-734.

[] Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity, 2009, 30(2): 180-192.

[] Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3–K9. Genes & Development, 2005, 19(7): 815-826.

[] Tang G, Guo J, Zhu Y, Huang Z, Liu T, Cai J, Yu L, Wang Z. Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. International Journal of Oncology, 2018, 52(6): 1899-1911.

[] Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature Reviews Cancer, 2013, 13(7): 497-510.

[] Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y. Histone demethylation by a family of JmjC domain-containing proteins. Nature, 2006, 439(7078): 811-816.

[] Uytterhoeven V, Lauwers E, Maes I, Miskiewicz K, Melo MN, Swerts J, Kuenen S, Wittocx R, Corthout N, Marrink SJ, Munck S, Verstreken P. Hsc70-4 deforms membranes to promote synaptic protein turnover by endosomal microautophagy. Neuron, 2015, 88(4): 735-748.

[] Venneti S, Kawakibi AR, Ji S, Waszak SM, Sweha SR, Mota M, Pun M, Deogharkar A, Chung C, Tarapore RS, Ramage S, Chi A, Wen PY, Arrillaga-Romany I, Batchelor TT, Butowski NA, Sumrall A, Shonka N, Harrison RA, de Groot J, et al. Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways. Cancer Discovery, 2023, 13(11): 2370-2393.

[] Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr Kinzler KW. Cancer genome landscapes. Science (New York, NY), 2013, 339(6127): 1546-1558.

[] Wang W, Wang Q, Huang DB, Sun QK, Wu SS, Zhao YJ, Jia W, Hu DS, He YF. Tumor-associated mesenchymal stem cells promote hepatocellular carcinoma metastasis via a DNM3OS/KDM6B/TIAM1 axis. Cancer Letters, 2021, 503: 19-31.

[] White E, DiPaola RS. The double-edged sword of autophagy modulation in cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 2009, 15(17): 5308-5316.

[] Wu C, Chen W, He J, Jin S, Liu Y, Yi Y, Gao Z, Yang J, Yang J, Cui J, Zhao W. Interplay of m⁶A and H3K27 trimethylation restrains inflammation during bacterial infection. Science Advances, 2020, 6(34).

[] Wu H, Chen X, Xiong J, Li Y, Li H, Ding X, Liu S, Chen S, Gao S, Zhu B. Histone methyltransferase G9a contributes to H3K27 methylation in vivo. Cell Research, 2011, 21(2): 365-367.

[] Wu Y, Hu L, Liang Y, Li J, Wang K, Chen X, Meng H, Guan X, Yang K, Bai Y. Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2. Molecular Cancer, 2017, 16(1): 150.

[] Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ. Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature, 2003, 421(6923): 652-656.

[] Xie Z, Klionsky DJ. Autophagosome formation: Core machinery and adaptations. Nature Cell Biology, 2007, 9(10): 1102-1109.

[] Xu K, Liu X, Wen B, Liu Y, Zhang W, Hu X, Chen L, Hang W, Chen J. GSK-J4, a specific histone lysine demethylase 6A inhibitor, ameliorates lipotoxicity to cardiomyocytes via preserving H3K27 methylation and reducing ferroptosis. Frontiers in Cardiovascular Medicine, 2022, 9.

[] Xu L, Feng J, Tang H, Dong Y, Shu M, Chen X. Chidamide epigenetically represses autophagy and exerts cooperative antimyeloma activity with bortezomib. Cell Death & Disease, 2020, 11(4): 297.

[] Xu Y, Dong X, Qi P, Ye Y, Shen W, Leng L, Wang L, Li X, Luo X, Chen Y, Sun P, Xiang R, Li N. Sox2 Communicates with Tregs through CCL1 to promote the stemness property of breast cancer cells. Stem Cells (Dayton, Ohio), 2017, 35(12): 2351-2365.

[] Yamamoto M, Jin C, Hata T, Yasumizu Y, Zhang Y, Hong D, Maeda T, Miyo M, Hiraki M, Suzuki Y, Hinohara K, Rajabi H, Kufe D. MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells. Cancer Research, 2019, 79(8): 2031-2041.

[] Yang A, Jiao Y, Yang S, Deng M, Yang X, Mao C, Sun Y, Ding N, Li N, Zhang M, Jin S, Zhang H, Jiang Y. Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver. Cell Death & Disease, 2018, 9(2): 169.

[] Yang L, Ma DW, Cao YP, Li DZ, Zhou X, Feng JF, Bao J. PRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expression. Theranostics, 2021, 11(8): 3742-3759.

[] Yang MH, Zhao L, Wang L, Ou-Yang W, Hu SS, Li WL, Ai ML, Wang YQ, Han Y, Li TT, Ding YQ, Wang S. Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin β3 transcriptional activating and MAPK/AKT signalling. Molecular Cancer, 2019, 18(1): 31.

[] Yang Y, Hu L, Wang P, Hou H, Lin Y, Liu Y, Li Z, Gong R, Feng X, Zhou L, Zhang W, Dong Y, Yang H, Lin H, Wang Y, Chen CD, Xu Y. Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans. Cell Research, 2010, 20(8): 886-898.

[] Ying Y, Wang M, Chen Y, Li M, Ma C, Zhang J, Huang X, Jia M, Zeng J, Wang Y, Li L, Wang X, Tao Q, Shu XS. Zinc finger protein 280C contributes to colorectal tumorigenesis by maintaining epigenetic repression at H3K27me3-marked loci. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119(22).

[] Yoshimi A, Kurokawa M. Key roles of histone methyltransferase and demethylase in leukemogenesis. Journal of Cellular Biochemistry, 2011, 112(2): 415-424.

[] Yuan X, Gajan A, Chu Q, Xiong H, Wu K, Wu GS. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Reviews, 2018, 37(4): 733-748.

[] Zahoor M, Farhan H. Crosstalk of autophagy and the secretory pathway and its role in diseases. International Review of Cell and Molecular Biology, 2018, 337: 153-184.

[] Zhang C, Gao S, Molascon AJ, Liu Y, Andrews PC. Quantitative proteomics reveals histone modifications in crosstalk with H3 lysine 27 methylation. Molecular & Cellular Proteomics: MCP, 2014, 13(3): 749-759.

[] Zhang C, Molascon AJ, Gao S, Liu Y, Andrews PC. Quantitative proteomics reveals that the specific methyltransferases Txr1p and Ezl2p differentially affect the mono-, di- and trimethylation states of histone H3 lysine 27 (H3K27). Molecular & Cellular Proteomics: MCP, 2013, 12(6): 1678-1688.

[] Zhang M, Zheng J, Nussinov R, Ma B. Release of cytochrome c from Bax pores at the mitochondrial membrane. Scientific Reports, 2017, 7(1): 2635.

[] Zhao J, Jin W, Yi K, Wang Q, Zhou J, Tan Y, Xu C, Xiao M, Hong B, Xu F, Zhang K, Kang C. Combination LSD1 and HOTAIR-EZH2 inhibition disrupts cell cycle processes and induces apoptosis in glioblastoma cells. Pharmacological Research, 2021, 171.

[] Zhong Y, Li L, Chen Z, Diao S, He Y, Zhang Z, Zhang H, Yuan X, Li J. MIR143 inhibits steroidogenesis and induces apoptosis repressed by H3K27me3 in granulosa cells. Frontiers in Cell and Developmental Biology, 2020, 8.

[] Zhu Q, Yang Q, Lu X, Wang H, Tong L, Li Z, Liu G, Bao Y, Xu X, Gu L, Yuan J, Liu X, Zhu WG. SETD2-mediated H3K14 trimethylation promotes ATR activation and stalled replication fork restart in response to DNA replication stress. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118(23).

[] Zhu Y, Fu J, Yang H, Pan Y, Yao L, Xue X. Hyperoxia-induced methylation decreases RUNX3 in a newborn rat model of bronchopulmonary dysplasia. Respiratory Research, 2015, 16(1): 75.

Funding

National Natural Science Foundation of China(82002986)