Multidimensional Roles of EZH2 and Its Therapeutic Potential in Cancer Therapy

Hui Yin; Jinna Tan; Jiaqian He; Mingfen Li; Hongsheng Lin

doi:10.71321/q01vae55

Authors

Hui Yin First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China,530022.
Jinna Tan First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China,530022.
Jiaqian He First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China,530022.
Mingfen Li Laboratory Department, First Affiliated Hospital, Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi, China, 530012.
Hongsheng Lin Laboratory Department, First Affiliated Hospital, Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi, China, 530012.

DOI:

https://doi.org/10.71321/q01vae55

Keywords:

EZH2, epigenetic modification, methylation, H3K27me3, cancer

Abstract

Enhancer of zeste homolog 2 (EZH2), a core member of the Polycomb Group (PcG) family, is a pivotal epigenetic regulator. As the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), EZH2 mediates trimethylation of histone H3 lysine 27 (H3K27me3), leading to chromatin condensation and altered expression of downstream genes. This mechanism enables EZH2 to exert multidimensional roles in development, tumors, immunity, and the nervous system. Given its critical role in epigenetic regulation and multidimensional oncogenesis, EZH2 has emerged as a hot target for cancer therapy. This review summarizes EZH2's regulatory functions and specific pro-tumorigenic mechanisms, detailing its roles in epigenetic regulation, tumor proliferation and metastasis, tumor microenvironment, stemness maintenance, drug resistance, metabolic reprogramming, and dysregulated signaling pathways, aiming to inspire new perspectives in cancer treatment research.

References

[1] TANG J, ZHUANG S. Histone acetylation and DNA methylation in ischemia/reperfusion injury [J]. Clin Sci (Lond), 2019, 133(4): 597-609.http://doi.org/10.1042/cs20180465

[2] ZHANG J, CHEN W, MA W, HAN C, SONG K, KWON H, et al. EZH2 Promotes Cholangiocarcinoma Development and Progression through Histone Methylation and microRNA-Mediated Down-Regulation of Tumor Suppressor Genes [J]. Am J Pathol, 2022, 192(12): 1712-24.http://doi.org/10.1016/j.ajpath.2022.08.008

[3] WANG K, JIANG X, JIANG Y, LIU J, DU Y, ZHANG Z, et al. EZH2-H3K27me3-mediated silencing of mir-139-5p inhibits cellular senescence in hepatocellular carcinoma by activating TOP2A [J]. J Exp Clin Cancer Res, 2023, 42(1): 320.http://doi.org/10.1186/s13046-023-02855-2

[4] KIM E, KIM M, WOO D H, SHIN Y, SHIN J, CHANG N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells [J]. Cancer Cell, 2013, 23(6): 839-52.http://doi.org/10.1016/j.ccr.2013.04.008

[5] VASANTHAKUMAR A, XU D, LUN A T, KUEH A J, VAN GISBERGEN K P, IANNARELLA N, et al. A non-canonical function of Ezh2 preserves immune homeostasis [J]. EMBO Rep, 2017, 18(4): 619-31.http://doi.org/10.15252/embr.201643237

[6] LIU Q, WANG G, LI Q, JIANG W, KIM J S, WANG R, et al. Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer [J]. Int J Cancer, 2019, 145(2): 415-26.http://doi.org/10.1002/ijc.32118

[7] YANG Z, WEI B, QIAO A, YANG P, CHEN W, ZHEN D, et al. A novel EZH2/NXPH4/CDKN2A axis is involved in regulating the proliferation and migration of non-small cell lung cancer cells [J]. Biosci Biotechnol Biochem, 2022, 86(3): 340-50.http://doi.org/10.1093/bbb/zbab217

[8] CHEN J, HONG J H, HUANG Y, LIU S, YIN J, DENG P, et al. EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer [J]. Mol Cancer, 2023, 22(1): 85.http://doi.org/10.1186/s12943-023-01786-y

[9] PAWLYN C, BRIGHT M D, BUROS A F, STEIN C K, WALTERS Z, ARONSON L I, et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control [J]. Blood Cancer J, 2017, 7(3): e549.http://doi.org/10.1038/bcj.2017.27

[10] XU X, GU J, DING X, GE G, ZANG X, JI R, et al. LINC00978 promotes the progression of hepatocellular carcinoma by regulating EZH2-mediated silencing of p21 and E-cadherin expression [J]. Cell Death Dis, 2019, 10(10): 752.http://doi.org/10.1038/s41419-019-1990-6

[11] CHEN W M, CHEN W D, JIANG X M, JIA X F, WANG H M, ZHANG Q J, et al. HOX transcript antisense intergenic RNA represses E-cadherin expression by binding to EZH2 in gastric cancer [J]. World J Gastroenterol, 2017, 23(33): 6100-10.http://doi.org/10.3748/wjg.v23.i33.6100

[12] ZOU G, HUANG Y, ZHANG S, KO K P, KIM B, ZHANG J, et al. E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming [J]. J Exp Med, 2024, 221(4).http://doi.org/10.1084/jem.20230561

[13] ZHUANG C, WANG P, HUANG D, XU L, WANG X, WANG L, et al. A double-negative feedback loop between EZH2 and miR-26a regulates tumor cell growth in hepatocellular carcinoma [J]. Int J Oncol, 2016, 48(3): 1195-204.http://doi.org/10.3892/ijo.2016.3336

[14] BAI B, LIU Y, FU X M, QIN H Y, LI G K, WANG H C, et al. Dysregulation of EZH2/miR-138-5p Axis Contributes to Radiosensitivity in Hepatocellular Carcinoma Cell by Downregulating Hypoxia-Inducible Factor 1 Alpha (HIF-1α) [J]. Oxid Med Cell Longev, 2022, 2022: 7608712.http://doi.org/10.1155/2022/7608712

[15] ZHAO J, LI H, ZHAO S, WANG E, ZHU J, FENG D, et al. Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling [J]. Mol Cancer, 2021, 20(1): 46.http://doi.org/10.1186/s12943-021-01343-5

[16] XING C Y, ZHANG Y Z, HU W, ZHAO L Y. LINC00313 facilitates osteosarcoma carcinogenesis and metastasis through enhancing EZH2 mRNA stability and EZH2-mediated silence of PTEN expression [J]. Cell Mol Life Sci, 2022, 79(7): 382.http://doi.org/10.1007/s00018-022-04376-1

[17] SOUROULLAS G P, JECK W R, PARKER J S, SIMON J M, LIU J Y, PAULK J, et al. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation [J]. Nat Med, 2016, 22(6): 632-40.http://doi.org/10.1038/nm.4092

[18] SNEERINGER C J, SCOTT M P, KUNTZ K W, KNUTSON S K, POLLOCK R M, RICHON V M, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas [J]. Proc Natl Acad Sci U S A, 2010, 107(49): 20980-5.http://doi.org/10.1073/pnas.1012525107

[19] SCORE J, HIDALGO-CURTIS C, JONES A V, WINKELMANN N, SKINNER A, WARD D, et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms [J]. Blood, 2012, 119(5): 1208-13.http://doi.org/10.1182/blood-2011-07-367243

[20] ZHANG D, QIU Y, ZHANG W, DU D, LIU Y, LIU L, et al. Homeobox B9 promotes the invasion and metastasis of hepatocellular carcinoma cells via the EZH2-MIR203A-SNAI2 axis [J]. J Transl Med, 2024, 22(1): 918.http://doi.org/10.1186/s12967-024-05690-x

[21] ZHENG M, JIANG Y P, CHEN W, LI K D, LIU X, GAO S Y, et al. Snail and Slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma [J]. Oncotarget, 2015, 6(9): 6797-810.http://doi.org/10.18632/oncotarget.3180

[22] LU L, LUO F, LIU Y, LIU X, SHI L, LU X, et al. Posttranscriptional silencing of the lncRNA MALAT1 by miR-217 inhibits the epithelial-mesenchymal transition via enhancer of zeste homolog 2 in the malignant transformation of HBE cells induced by cigarette smoke extract [J]. Toxicol Appl Pharmacol, 2015, 289(2): 276-85.http://doi.org/10.1016/j.taap.2015.09.016

[23] ZHANG K, FANG T, SHAO Y, WU Y. TGF-β-MTA1-SMAD7-SMAD3-SOX4-EZH2 Signaling Axis Promotes Viability, Migration, Invasion and EMT of Hepatocellular Carcinoma Cells [J]. Cancer Manag Res, 2021, 13: 7087-99.http://doi.org/10.2147/cmar.S297765

[24] ZANG C, NIE F Q, WANG Q, SUN M, LI W, HE J, et al. Long non-coding RNA LINC01133 represses KLF2, P21 and E-cadherin transcription through binding with EZH2, LSD1 in non small cell lung cancer [J]. Oncotarget, 2016, 7(10): 11696-707.http://doi.org/10.18632/oncotarget.7077

[25] ZHANG S, LIAO W, WU Q, HUANG X, PAN Z, CHEN W, et al. LINC00152 upregulates ZEB1 expression and enhances epithelial-mesenchymal transition and oxaliplatin resistance in esophageal cancer by interacting with EZH2 [J]. Cancer Cell Int, 2020, 20(1): 569.http://doi.org/10.1186/s12935-020-01620-1

[26] LIN Y H, WU M H, LIU Y C, LYU P C, YEH C T, LIN K H. LINC01348 suppresses hepatocellular carcinoma metastasis through inhibition of SF3B3-mediated EZH2 pre-mRNA splicing [J]. Oncogene, 2021, 40(28): 4675-85.http://doi.org/10.1038/s41388-021-01905-3

[27] VERMA A, SINGH A, SINGH M P, NENGROO M A, SAINI K K, SATRUSAL S R, et al. EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis [J]. Nat Commun, 2022, 13(1): 7344.http://doi.org/10.1038/s41467-022-35059-x

[28] CARLSON S M, GOZANI O. Emerging technologies to map the protein methylome [J]. J Mol Biol, 2014, 426(20): 3350-62.http://doi.org/10.1016/j.jmb.2014.04.024

[29] LIU F, MA F, WANG Y, HAO L, ZENG H, JIA C, et al. PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis [J]. Nat Cell Biol, 2017, 19(11): 1358-70.http://doi.org/10.1038/ncb3630

[30] HUANG C, HU F, SONG D, SUN X, LIU A, WU Q, et al. EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis [J]. J Clin Invest, 2022, 132(5).http://doi.org/10.1172/jci152394

[31] HU X, LIU Y, SHEN H, ZHANG T, LIANG T. MTF2 facilitates the advancement of osteosarcoma through mediating EZH2/SFRP1/Wnt signaling [J]. J Orthop Surg Res, 2024, 19(1): 467.http://doi.org/10.1186/s13018-024-04965-9

[32] CHEN W, WANG H T, JI J F, WANG Z Y, SHI T, WU M H, et al. Epigenetic network of EZH2/SFRP1/Wnt in the epithelial-mesenchymal transition of laryngeal carcinoma cells [J]. Neoplasma, 2022, 69(3): 680-90.http://doi.org/10.4149/neo_2022_211208N1749

[33] ZHANG Y, LIN C, LIAO G, LIU S, DING J, TANG F, et al. MicroRNA-506 suppresses tumor proliferation and metastasis in colon cancer by directly targeting the oncogene EZH2 [J]. Oncotarget, 2015, 6(32): 32586-601.http://doi.org/10.18632/oncotarget.5309

[34] LIANG G, HAN L, QU M, XUE J, XU D, WU X, et al. Down-regulation of EZH2 genes targeting RUNX3 affects proliferation, invasion, and metastasis of human colon cancer cells by Wnt/β-catenin signaling pathway [J]. Aging (Albany NY), 2023, 15(23): 13655-68.http://doi.org/10.18632/aging.205197

[35] REN L, DENG H, JIANG Y, LIU C. Dual-Regulated Mechanism of EZH2 and KDM6A on SALL4 Modulates Tumor Progression via Wnt/β-Catenin Pathway in Gastric Cancer [J]. Dig Dis Sci, 2023, 68(4): 1292-305.http://doi.org/10.1007/s10620-022-07790-4

[36] ZHANG J, LIU G, JIN H, LI X, LI N, YIN Q, et al. MicroRNA-137 targets EZH2 to exert suppressive functions in uveal melanoma via regulation of Wnt/β-catenin signaling and epithelial-to-mesenchymal transition [J]. J buon, 2021, 26(1): 173-181.

[37] ZINGG D, DEBBACHE J, PEñA-HERNáNDEZ R, ANTUNES A T, SCHAEFER S M, CHENG P F, et al. EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation [J]. Cancer Cell, 2018, 34(1): 69-84.e14.http://doi.org/10.1016/j.ccell.2018.06.001

[38] XU H, ZHAO G, ZHANG Y, JIANG H, WANG W, ZHAO D, et al. Mesenchymal stem cell-derived exosomal microRNA-133b suppresses glioma progression via Wnt/β-catenin signaling pathway by targeting EZH2 [J]. Stem Cell Res Ther, 2019, 10(1): 381.http://doi.org/10.1186/s13287-019-1446-z

[39] LIAN R, MA H, WU Z, ZHANG G, JIAO L, MIAO W, et al. EZH2 promotes cell proliferation by regulating the expression of RUNX3 in laryngeal carcinoma [J]. Mol Cell Biochem, 2018, 439(1-2): 35-43.http://doi.org/10.1007/s11010-017-3133-7

[40] CHEN Q, ZHENG P S, YANG W T. EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma [J]. Oncotarget, 2016, 7(24): 36115-29.http://doi.org/10.18632/oncotarget.8741

[41] ZHANG J J, CHEN J T, HUA L, YAO K H, WANG C Y. miR-98 inhibits hepatocellular carcinoma cell proliferation via targeting EZH2 and suppressing Wnt/β-catenin signaling pathway [J]. Biomed Pharmacother, 2017, 85: 472-8.http://doi.org/10.1016/j.biopha.2016.11.053

[42] WANG Y F, YU L, HU Z L, FANG Y F, SHEN Y Y, SONG M F, et al. Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer [J]. Cell Death Dis, 2022, 13(8): 748.http://doi.org/10.1038/s41419-022-05169-x

[43] ISSHIKI Y, CHEN X, TEATER M, KARAGIANNIDIS I, NAM H, CAI W, et al. EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function [J]. Cancer Cell, 2025, 43(1): 49-68.e9.http://doi.org/10.1016/j.ccell.2024.11.006

[44] PORAZZI P, NASON S, YANG Z, CARTURAN A, GHILARDI G, GURUPRASAD P, et al. EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models [J]. Cancer Cell, 2025, 43(3): 537-51.e7.http://doi.org/10.1016/j.ccell.2025.01.013

[45] HUANG Z, TANG Y, ZHANG J, HUANG J, CHENG R, GUO Y, et al. Hypoxia makes EZH2 inhibitor not easy-advances of crosstalk between HIF and EZH2 [J]. Life Metab, 2024, 3(4).http://doi.org/10.1093/lifemeta/loae017

[46] HWANG-VERSLUES W W, CHANG P H, JENG Y M, KUO W H, CHIANG P H, CHANG Y C, et al. Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy [J]. Proc Natl Acad Sci U S A, 2013, 110(30): 12331-6.http://doi.org/10.1073/pnas.1222684110

[47] SHAN L, ZHOU X, LIU X, WANG Y, SU D, HOU Y, et al. FOXK2 Elicits Massive Transcription Repression and Suppresses the Hypoxic Response and Breast Cancer Carcinogenesis [J]. Cancer Cell, 2016, 30(5): 708-22.http://doi.org/10.1016/j.ccell.2016.09.010

[48] SUN J, CAI X, YUNG M M, ZHOU W, LI J, ZHANG Y, et al. miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer [J]. Oncogene, 2019, 38(4): 564-80.http://doi.org/10.1038/s41388-018-0459-x

[49] XU S, LI X, LI L, WANG Y, GENG C, GUO F, et al. CTCF-silenced miR-137 contributes to EMT and radioresistance in esophageal squamous cell carcinoma [J]. Cancer Cell Int, 2021, 21(1): 155.http://doi.org/10.1186/s12935-020-01740-8

[50] LIU H, LI W, YU X, GAO F, DUAN Z, MA X, et al. EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis [J]. Oncotarget, 2016, 7(35): 56338-54.http://doi.org/10.18632/oncotarget.10841

[51] ZHONG J, YANG X, CHEN J, HE K, GAO X, WU X, et al. Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands [J]. Nat Commun, 2022, 13(1): 4795.http://doi.org/10.1038/s41467-022-32311-2

[52] LIU J, YANG L, LIU X, LIU L, LIU M, FENG X, et al. lncRNA HOTTIP Recruits EZH2 to Inhibit PTEN Expression and Participates in IM Resistance in Chronic Myeloid Leukemia [J]. Stem Cells Int, 2022, 2022: 9993393.http://doi.org/10.1155/2022/9993393

[53] HAYWARD N K, WILMOTT J S, WADDELL N, JOHANSSON P A, FIELD M A, NONES K, et al. Whole-genome landscapes of major melanoma subtypes [J]. Nature, 2017, 545(7653): 175-80.http://doi.org/10.1038/nature22071

[54] HODIS E, WATSON I R, KRYUKOV G V, AROLD S T, IMIELINSKI M, THEURILLAT J P, et al. A landscape of driver mutations in melanoma [J]. Cell, 2012, 150(2): 251-63.http://doi.org/10.1016/j.cell.2012.06.024

[55] SINI M C, DONEDDU V, PALIOGIANNIS P, CASULA M, COLOMBINO M, MANCA A, et al. Genetic alterations in main candidate genes during melanoma progression [J]. Oncotarget, 2018, 9(9): 8531-41.http://doi.org/10.18632/oncotarget.23989

[56] TANDA E T, VANNI I, BOUTROS A, ANDREOTTI V, BRUNO W, GHIORZO P, et al. Current State of Target Treatment in BRAF Mutated Melanoma [J]. Front Mol Biosci, 2020, 7: 154.http://doi.org/10.3389/fmolb.2020.00154

[57] ZHANG Y, DU X L, WANG C J, LIN D C, RUAN X, FENG Y B, et al. Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells [J]. Gastroenterology, 2012, 142(3): 521-30.e3.http://doi.org/10.1053/j.gastro.2011.11.023

[58] UEBEL A, KEWITZ-HEMPEL S, WILLSCHER E, GEBHARDT K, SUNDERKöTTER C, GERLOFF D. Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma [J]. Int J Mol Sci, 2023, 24(3).http://doi.org/10.3390/ijms24031963

[59] YANG C, GU Y, GE Z, SONG C. Targeting EZH2 Promotes Chemosensitivity of BCL-2 Inhibitor through Suppressing PI3K and c-KIT Signaling in Acute Myeloid Leukemia [J]. Int J Mol Sci, 2022, 23(19).http://doi.org/10.3390/ijms231911393

[60] WANG X, XIE Z, LOU Z, CHEN Y, HUANG S, REN Y, et al. Regulation of the PTEN/PI3K/AKT pathway in RCC using the active compounds of natural products in vitro [J]. Mol Med Rep, 2021, 24(5).http://doi.org/10.3892/mmr.2021.12406

[61] SU Y, WANG B, HUANG J, HUANG M, LIN T. YTHDC1 positively regulates PTEN expression and plays a critical role in cisplatin resistance of bladder cancer [J]. Cell Prolif, 2023, 56(7): e13404.http://doi.org/10.1111/cpr.13404

[62] DENG X, KONG F, LI S, JIANG H, DONG L, XU X, et al. A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer [J]. Cell Death Dis, 2021, 12(5): 485.http://doi.org/10.1038/s41419-021-03753-1

[63] YU T, ZHOU F, TIAN W, XU R, WANG B, ZENG A, et al. EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma [J]. Oncogene, 2023, 42(6): 461-70.http://doi.org/10.1038/s41388-022-02570-w

[64] YANG Q, ZHAO S, SHI Z, CAO L, LIU J, PAN T, et al. Chemotherapy-elicited exosomal miR-378a-3p and miR-378d promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling [J]. J Exp Clin Cancer Res, 2021, 40(1): 120.http://doi.org/10.1186/s13046-021-01901-1

[65] ZHANG Q, SHI Y, LIU S, YANG W, CHEN H, GUO N, et al. EZH2/G9a interact to mediate drug resistance in non-small-cell lung cancer by regulating the SMAD4/ERK/c-Myc signaling axis [J]. Cell Rep, 2024, 43(2): 113714.http://doi.org/10.1016/j.celrep.2024.113714

[66] VESCHI V, VERONA F, THIELE C J. Cancer Stem Cells and Neuroblastoma: Characteristics and Therapeutic Targeting Options [J]. Front Endocrinol (Lausanne), 2019, 10: 782.http://doi.org/10.3389/fendo.2019.00782

[67] KAMIJO T. Role of stemness-related molecules in neuroblastoma [J]. Pediatr Res, 2012, 71(4 Pt 2): 511-5.http://doi.org/10.1038/pr.2011.54

[68] ADHIKARY G, GRUN D, BALASUBRAMANIAN S, KERR C, HUANG J M, ECKERT R L. Survival of skin cancer stem cells requires the Ezh2 polycomb group protein [J]. Carcinogenesis, 2015, 36(7): 800-10.http://doi.org/10.1093/carcin/bgv064

[69] EL BABA R, PASQUEREAU S, HAIDAR AHMAD S, DIAB-ASSAF M, HERBEIN G. Oncogenic and Stemness Signatures of the High-Risk HCMV Strains in Breast Cancer Progression [J]. Cancers (Basel), 2022, 14(17).http://doi.org/10.3390/cancers14174271

[70] LIU H, SUN Q, SUN Y, ZHANG J, YUAN H, PANG S, et al. MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation [J]. Mol Cancer Res, 2017, 15(9): 1275-86.http://doi.org/10.1158/1541-7786.Mcr-17-0105

[71] CHEN L, ZHANG M, FANG L, YANG X, CAO N, XU L, et al. Coordinated regulation of the ribosome and proteasome by PRMT1 in the maintenance of neural stemness in cancer cells and neural stem cells [J]. J Biol Chem, 2021, 297(5): 101275.http://doi.org/10.1016/j.jbc.2021.101275

[72] VAN VLERKEN L E, KIEFER C M, MOREHOUSE C, LI Y, GROVES C, WILSON S D, et al. EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter [J]. Stem Cells Transl Med, 2013, 2(1): 43-52.http://doi.org/10.5966/sctm.2012-0036

[73] SUVà M L, RIGGI N, JANISZEWSKA M, RADOVANOVIC I, PROVERO P, STEHLE J C, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance [J]. Cancer Res, 2009, 69(24): 9211-8.http://doi.org/10.1158/0008-5472.Can-09-1622

[74] ZONG X, NEPHEW K P. Ovarian Cancer Stem Cells: Role in Metastasis and Opportunity for Therapeutic Targeting [J]. Cancers (Basel), 2019, 11(7).http://doi.org/10.3390/cancers11070934

[75] GORODETSKA I, LUKIYANCHUK V, PEITZSCH C, KOZERETSKA I, DUBROVSKA A. BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype [J]. Int J Cancer, 2019, 145(11): 2974-85.http://doi.org/10.1002/ijc.32323

[76] CHEN Z, TANG W, ZHOU Y, HE Z. The role of LINC01419 in regulating the cell stemness in lung adenocarcinoma through recruiting EZH2 and regulating FBP1 expression [J]. Biol Direct, 2022, 17(1): 23.http://doi.org/10.1186/s13062-022-00336-8

[77] TSENG C F, CHEN L T, WANG H D, LIU Y H, SHIAH S G. Transcriptional suppression of Dicer by HOXB-AS3/EZH2 complex dictates sorafenib resistance and cancer stemness [J]. Cancer Sci, 2022, 113(5): 1601-12.http://doi.org/10.1111/cas.15319

[78] ZHANG Y, TANG B, SONG J, YU S, LI Y, SU H, et al. Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2-mediated ATOH8 transcriptional repression [J]. J Exp Clin Cancer Res, 2019, 38(1): 92.http://doi.org/10.1186/s13046-019-1106-2

[79] CAI L, LIU Y, LI Y, LIU B, CAO Y, YANG W, et al. TRIM37 interacts with EZH2 to epigenetically suppress PTCH1 and regulate stemness in glioma stem cells through sonic hedgehog pathway [J]. J Neurooncol, 2024, 169(2): 269-79.http://doi.org/10.1007/s11060-024-04726-y

[80] SANCHES J G P, SONG B, ZHANG Q, CUI X, YABASIN I B, NTIM M, et al. The Role of KDM2B and EZH2 in Regulating the Stemness in Colorectal Cancer Through the PI3K/AKT Pathway [J]. Front Oncol, 2021, 11: 637298.http://doi.org/10.3389/fonc.2021.637298

[81] MARIE S K, SHINJO S M. Metabolism and brain cancer [J]. Clinics (Sao Paulo), 2011, 66 Suppl 1(Suppl 1): 33-43.http://doi.org/10.1590/s1807-59322011001300005

[82] LIU Q, WANG L, WANG Z, YANG Y, TIAN J, LIU G, et al. GRIM-19 opposes reprogramming of glioblastoma cell metabolism via HIF1α destabilization [J]. Carcinogenesis, 2013, 34(8): 1728-36.http://doi.org/10.1093/carcin/bgt125

[83] PASCAL L E, AI J, RIGATTI L H, LIPTON A K, XIAO W, GNARRA J R, et al. EAF2 loss enhances angiogenic effects of Von Hippel-Lindau heterozygosity on the murine liver and prostate [J]. Angiogenesis, 2011, 14(3): 331-43.http://doi.org/10.1007/s10456-011-9217-1

[84] PANG B, ZHENG X R, TIAN J X, GAO T H, GU G Y, ZHANG R, et al. EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling [J]. Oncotarget, 2016, 7(29): 45134-43.http://doi.org/10.18632/oncotarget.9761

[85] VANTAKU V, PUTLURI V, BADER D A, MAITY S, MA J, ARNOLD J M, et al. Epigenetic loss of AOX1 expression via EZH2 leads to metabolic deregulations and promotes bladder cancer progression [J]. Oncogene, 2020, 39(40): 6265-85.http://doi.org/10.1038/s41388-019-0902-7

[86] CURRIE E, SCHULZE A, ZECHNER R, WALTHER T C, FARESE R V, JR. Cellular fatty acid metabolism and cancer [J]. Cell Metab, 2013, 18(2): 153-61.http://doi.org/10.1016/j.cmet.2013.05.017

[87] ZHANG Y, WU M J, LU W C, LI Y C, CHANG C J, YANG J Y. Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer [J]. Cell Metab, 2024, 36(1): 193-208.e8.http://doi.org/10.1016/j.cmet.2023.12.003

[88] BAKHTIARI M, JORDAN S C, MUMME H L, SHARMA R, SHANMUGAM M, BHASIN S S, et al. ARMH1 is a novel marker associated with poor pediatric AML outcomes that affect the fatty acid synthesis and cell cycle pathways [J]. Front Oncol, 2024, 14: 1445173.http://doi.org/10.3389/fonc.2024.1445173

[89] SAHU U, MULLARKEY M P, MURPHY S A, ANDERSON J C, PUTLURI V, KAMAL A H M, et al. IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity [J]. Nat Commun, 2025, 16(1): 3874.http://doi.org/10.1038/s41467-025-58911-2

[90] LIU Y, TU C E, GUO X, WU C, GU C, LAI Q, et al. Tumor-suppressive function of EZH2 is through inhibiting glutaminase [J]. Cell Death Dis, 2021, 12(11): 975.http://doi.org/10.1038/s41419-021-04212-7

[91] PAPATHANASSIU A E, KO J H, IMPRIALOU M, BAGNATI M, SRIVASTAVA P K, VU H A, et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases [J]. Nat Commun, 2017, 8: 16040.http://doi.org/10.1038/ncomms16040

[92] LU H, LI G, ZHOU C, JIN W, QIAN X, WANG Z, et al. Regulation and role of post-translational modifications of enhancer of zeste homologue 2 in cancer development [J]. Am J Cancer Res, 2016, 6(12): 2737-54

[93] T W M F, ISLAM J M M, HIGASHI R M, LIN P, BRAINSON C F, LANE A N. Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions [J]. J Biol Chem, 2024, 300(1): 105485.http://doi.org/10.1016/j.jbc.2023.105485

[94] CANTLEY L C. The phosphoinositide 3-kinase pathway [J]. Science, 2002, 296(5573): 1655-7.http://doi.org/10.1126/science.296.5573.1655

[95] WANG X Q, SUN P, PALLER A S. Inhibition of integrin-linked kinase/protein kinase B/Akt signaling: mechanism for ganglioside-induced apoptosis [J]. J Biol Chem, 2001, 276(48): 44504-11.http://doi.org/10.1074/jbc.M106563200

[96] LI Y, SONG Y H, MOHLER J, DELAFONTAINE P. ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression [J]. Am J Physiol Heart Circ Physiol, 2006, 290(5): H2116-23.http://doi.org/10.1152/ajpheart.00551.2005

[97] TIAN Y, CHEN Z H, WU P, ZHANG D, MA Y, LIU X F, et al. MIR497HG-Derived miR-195 and miR-497 Mediate Tamoxifen Resistance via PI3K/AKT Signaling in Breast Cancer [J]. Adv Sci (Weinh), 2023, 10(12): e2204819.http://doi.org/10.1002/advs.202204819

[98] LI H, SHEN X, MA M, LIU W, YANG W, WANG P, et al. ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway [J]. J Exp Clin Cancer Res, 2021, 40(1): 340.http://doi.org/10.1186/s13046-021-02146-8

[99] KONG C, WU M, LU Q, KE B, XIE J, LI A. PI3K/AKT confers intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia [J]. Leuk Res, 2024, 144: 107548.http://doi.org/10.1016/j.leukres.2024.107548

[100] DAI Q, ZHANG T, PAN J, LI C. LncRNA UCA1 promotes cisplatin resistance in gastric cancer via recruiting EZH2 and activating PI3K/AKT pathway [J]. J Cancer, 2020, 11(13): 3882-92.http://doi.org/10.7150/jca.43446

[101] CHEN J, WANG F, XU H, XU L, CHEN D, WANG J, et al. Long Non-Coding RNA SNHG1 Regulates the Wnt/β-Catenin and PI3K/AKT/mTOR Signaling Pathways via EZH2 to Affect the Proliferation, Apoptosis, and Autophagy of Prostate Cancer Cell [J]. Front Oncol, 2020, 10: 552907.http://doi.org/10.3389/fonc.2020.552907

[102] XU K, WU Z J, GRONER A C, HE H H, CAI C, LIS R T, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent [J]. Science, 2012, 338(6113): 1465-9.http://doi.org/10.1126/science.1227604

[103] WEI X, GUO J, LI Q, JIA Q, JING Q, LI Y, et al. Bach1 regulates self-renewal and impedes mesendodermal differentiation of human embryonic stem cells [J]. Sci Adv, 2019, 5(3): eaau7887.http://doi.org/10.1126/sciadv.aau7887

[104] BASU S, CHERIYAMUNDATH S, BEN-ZE'EV A. Cell-cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis [J]. F1000Res, 2018, 7.http://doi.org/10.12688/f1000research.15782.1

[105] CAO W, LEE H, WU W, ZAMAN A, MCCORKLE S, YAN M, et al. Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma [J]. Nat Commun, 2020, 11(1): 3675.http://doi.org/10.1038/s41467-020-17227-z

[106] JUNG H Y, JUN S, LEE M, KIM H C, WANG X, JI H, et al. PAF and EZH2 induce Wnt/β-catenin signaling hyperactivation [J]. Mol Cell, 2013, 52(2): 193-205.http://doi.org/10.1016/j.molcel.2013.08.028

[107] YU D, WANG S, WANG J, ZHANG K, NIU Z, LIN N. EZH2-STAT3 signaling pathway regulates GSDMD-mediated pyroptosis in glioblastoma [J]. Cell Death Discov, 2024, 10(1): 341.http://doi.org/10.1038/s41420-024-02105-0

[108] ZHANG D, YANG X J, LUO Q D, FU D L, LI H L, LI H C, et al. EZH2 enhances the invasive capability of renal cell carcinoma cells via activation of STAT3 [J]. Mol Med Rep, 2018, 17(3): 3621-6.http://doi.org/10.3892/mmr.2017.8363

[109] ZHENG M, CAO M X, LUO X J, LI L, WANG K, WANG S S, et al. EZH2 promotes invasion and tumour glycolysis by regulating STAT3 and FoxO1 signalling in human OSCC cells [J]. J Cell Mol Med, 2019, 23(10): 6942-54.http://doi.org/10.1111/jcmm.14579

[110] LI C, SONG J, GUO Z, GONG Y, ZHANG T, HUANG J, et al. EZH2 Inhibitors Suppress Colorectal Cancer by Regulating Macrophage Polarization in the Tumor Microenvironment [J]. Front Immunol, 2022, 13: 857808.http://doi.org/10.3389/fimmu.2022.857808

[111] ZHOU X, CHEN H, HU Y, MA X, LI J, SHI Y, et al. Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization [J]. Cell Death Dis, 2023, 14(4): 253.http://doi.org/10.1038/s41419-023-05782-4

[112] FUJII S, TOKITA K, WADA N, ITO K, YAMAUCHI C, ITO Y, et al. MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes [J]. Oncogene, 2011, 30(39): 4118-28.http://doi.org/10.1038/onc.2011.118

[113] LIU K, NI J D, LI W Z, PAN B Q, YANG Y T, XIA Q, et al. The Sp1/FOXC1/HOTTIP/LATS2/YAP/β-catenin cascade promotes malignant and metastatic progression of osteosarcoma [J]. Mol Oncol, 2020, 14(10): 2678-95.http://doi.org/10.1002/1878-0261.12760

[114] LUO C, BALSA E, PERRY E A, LIANG J, TAVARES C D, VAZQUEZ F, et al. H3K27me3-mediated PGC1α gene silencing promotes melanoma invasion through WNT5A and YAP [J]. J Clin Invest, 2020, 130(2): 853-62.http://doi.org/10.1172/jci130038

[115] LO SARDO F, TURCO C, MESSINA B, SACCONI A, AUCIELLO F R, PULITO C, et al. The oncogenic axis YAP/MYC/EZH2 impairs PTEN tumor suppression activity enhancing lung tumorigenicity [J]. Cell Death Discov, 2024, 10(1): 452.http://doi.org/10.1038/s41420-024-02216-8

[116] JEONG G Y, PARK M K, CHOI H J, AN H W, PARK Y U, CHOI H J, et al. NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression [J]. Cancer Res, 2021, 81(1): 77-90.http://doi.org/10.1158/0008-5472.Can-20-0360

[117] QIAN X, ZHANG Y. EZH2 enhances proliferation and migration of trophoblast cell lines by blocking GADD45A-mediated p38/MAPK signaling pathway [J]. Bioengineered, 2022, 13(5): 12583-97.http://doi.org/10.1080/21655979.2022.2074620