Cancer Research and Treatment

The Korean Cancer Association (대한암학회)
권호 표지
DOI QR코드

DOI QR Code

Regulation and Role of EZH2 in Cancer

  • Yamaguchi, Hirohito (Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center) ;
  • Hung, Mien-Chie (Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center)
  • Received : 2014.05.09
  • Accepted : 2014.06.05
  • Published : 2014.07.15
⟨ Previous Next ⟩

Abstract

Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.

Keywords

Acknowledgement

Supported by : National Institutes of Health

References

  1. Morey L, Helin K. Polycomb group protein-mediated repression of transcription. Trends Biochem Sci. 2010;35:323-32. https://doi.org/10.1016/j.tibs.2010.02.009
  2. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009;10:697-708. https://doi.org/10.1038/nrn2731
  3. O'Meara MM, Simon JA. Inner workings and regulatory inputs that control Polycomb repressive complex 2. Chromosoma. 2012;121:221-34. https://doi.org/10.1007/s00412-012-0361-1
  4. Koh CM, Iwata T, Zheng Q, Bethel C, Yegnasubramanian S, De Marzo AM. Myc enforces overexpression of EZH2 in early prostatic neoplasia via transcriptional and post-transcriptional mechanisms. Oncotarget. 2011;2:669-83.
  5. Wang L, Zhang X, Jia LT, Hu SJ, Zhao J, Yang JD, et al. c-Mycmediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma. Hepatology. 2014;59:1850-63. https://doi.org/10.1002/hep.26720
  6. Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, et al. MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood. 2008;112:4202-12. https://doi.org/10.1182/blood-2008-03-147645
  7. Salvatori B, Iosue I, Djodji Damas N, Mangiavacchi A, Chiaretti S, Messina M, et al. Critical role of c-Myc in acute myeloid leukemia involving direct regulation of miR-26a and histone methyltransferase EZH2. Genes Cancer. 2011;2:585-92. https://doi.org/10.1177/1947601911416357
  8. Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009;69:9211-8. https://doi.org/10.1158/0008-5472.CAN-09-1622
  9. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003;22:5323-35. https://doi.org/10.1093/emboj/cdg542
  10. Kalashnikova EV, Revenko AS, Gemo AT, Andrews NP, Tepper CG, Zou JX, et al. ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. Cancer Res. 2010;70:9402-12. https://doi.org/10.1158/0008-5472.CAN-10-1199
  11. Duan Z, Zou JX, Yang P, Wang Y, Borowsky AD, Gao AC, et al. Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate via MLL histone methylase complex. Prostate. 2013;73:455-66. https://doi.org/10.1002/pros.22587
  12. Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM, et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci U S A. 2009;106:5324-9. https://doi.org/10.1073/pnas.0810759106
  13. Tiwari N, Tiwari VK, Waldmeier L, Balwierz PJ, Arnold P, Pachkov M, et al. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell. 2013;23:768-83. https://doi.org/10.1016/j.ccr.2013.04.020
  14. Garipov A, Li H, Bitler BG, Thapa RJ, Balachandran S, Zhang R. NF-YA underlies EZH2 upregulation and is essential for proliferation of human epithelial ovarian cancer cells. Mol Cancer Res. 2013;11:360-9. https://doi.org/10.1158/1541-7786.MCR-12-0661
  15. Lin YW, Ren LL, Xiong H, Du W, Yu YN, Sun TT, et al. Role of STAT3 and vitamin D receptor in EZH2-mediated invasion of human colorectal cancer. J Pathol. 2013;230:277-90. https://doi.org/10.1002/path.4179
  16. Kunderfranco P, Mello-Grand M, Cangemi R, Pellini S, Mensah A, Albertini V, et al. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer. PLoS One. 2010;5:e10547. https://doi.org/10.1371/journal.pone.0010547
  17. Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell. 2011;19:86-100. https://doi.org/10.1016/j.ccr.2010.10.035
  18. Fujii S, Tokita K, Wada N, Ito K, Yamauchi C, Ito Y, et al. MEKERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes. Oncogene. 2011;30:4118-28. https://doi.org/10.1038/onc.2011.118
  19. Esposito F, Tornincasa M, Pallante P, Federico A, Borbone E, Pierantoni GM, et al. Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2. J Clin Endocrinol Metab. 2012;97:E710-8. https://doi.org/10.1210/jc.2011-3068
  20. Zhang B, Liu XX, He JR, Zhou CX, Guo M, He M, et al. Pathologically decreased miR-26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. Carcinogenesis. 2011;32:2-9. https://doi.org/10.1093/carcin/bgq209
  21. Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q, et al. MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res. 2011;71:225-33. https://doi.org/10.1158/0008-5472.CAN-10-1850
  22. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695-9. https://doi.org/10.1126/science.1165395
  23. Friedman JM, Liang G, Liu CC, Wolff EM, Tsai YC, Ye W, et al. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 2009;69:2623-9. https://doi.org/10.1158/0008-5472.CAN-08-3114
  24. Wang HJ, Ruan HJ, He XJ, Ma YY, Jiang XT, Xia YJ, et al. MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 2010;46:2295-303. https://doi.org/10.1016/j.ejca.2010.05.012
  25. Banerjee R, Mani RS, Russo N, Scanlon CS, Tsodikov A, Jing X, et al. The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. Oncogene. 2011;30:4339-49. https://doi.org/10.1038/onc.2011.141
  26. Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, et al. miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget. 2010;1:710-20.
  27. Zhang JG, Guo JF, Liu DL, Liu Q, Wang JJ. MicroRNA-101 exerts tumor-suppressive functions in non-small cell lung cancer through directly targeting enhancer of zeste homolog 2. J Thorac Oncol. 2011;6:671-8. https://doi.org/10.1097/JTO.0b013e318208eb35
  28. Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A, et al. MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J. 2011;440:23-31. https://doi.org/10.1042/BJ20111006
  29. Qiu S, Huang D, Yin D, Li F, Li X, Kung HF, et al. Suppression of tumorigenicity by microRNA-138 through inhibition of EZH2-CDK4/6-pRb-E2F1 signal loop in glioblastoma multiforme. Biochim Biophys Acta. 2013;1832:1697-707. https://doi.org/10.1016/j.bbadis.2013.05.015
  30. Zhang H, Zhang H, Zhao M, Lv Z, Zhang X, Qin X, et al. MiR-138 inhibits tumor growth through repression of EZH2 in nonsmall cell lung cancer. Cell Physiol Biochem. 2013;31:56-65. https://doi.org/10.1159/000343349
  31. Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One. 2012;7:e33729. https://doi.org/10.1371/journal.pone.0033729
  32. Cai K, Wan Y, Sun G, Shi L, Bao X, Wang Z. Let-7a inhibits proliferation and induces apoptosis by targeting EZH2 in nasopharyngeal carcinoma cells. Oncol Rep. 2012;28:2101-6. https://doi.org/10.3892/or.2012.2027
  33. Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 2012;61:278-89. https://doi.org/10.1136/gut.2011.239145
  34. Xie L, Zhang Z, Tan Z, He R, Zeng X, Xie Y, et al. microRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer. Mol Cell Biochem. 2014 Mar 22 [Epub]. http://dx.doi.org/10.1007/s11010-014-2028-0.
  35. Huang SD, Yuan Y, Zhuang CW, Li BL, Gong DJ, Wang SG, et al. MicroRNA-98 and microRNA-214 post-transcriptionally regulate enhancer of zeste homolog 2 and inhibit migration and invasion in human esophageal squamous cell carcinoma. Mol Cancer. 2012;11:51. https://doi.org/10.1186/1476-4598-11-51
  36. Alajez NM, Shi W, Hui AB, Bruce J, Lenarduzzi M, Ito E, et al. Enhancer of Zeste homolog 2 (EZH2) is overexpressed in recurrent nasopharyngeal carcinoma and is regulated by miR-26a, miR-101, and miR-98. Cell Death Dis. 2010;1:e85. https://doi.org/10.1038/cddis.2010.64
  37. Luo C, Tetteh PW, Merz PR, Dickes E, Abukiwan A, Hotz-Wagenblatt A, et al. miR-137 inhibits the invasion of melanoma cells through downregulation of multiple oncogenic target genes. J Invest Dermatol. 2013;133:768-75. https://doi.org/10.1038/jid.2012.357
  38. Guo Y, Ying L, Tian Y, Yang P, Zhu Y, Wang Z, et al. miR-144 downregulation increases bladder cancer cell proliferation by targeting EZH2 and regulating Wnt signaling. FEBS J. 2013;280:4531-8. https://doi.org/10.1111/febs.12417
  39. Xia H, Ooi LL, Hui KM. MiR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS One. 2012;7:e44206. https://doi.org/10.1371/journal.pone.0044206
  40. Shen J, Xia W, Khotskaya YB, Huo L, Nakanishi K, Lim SO, et al. EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. Nature. 2013;497:383-7. https://doi.org/10.1038/nature12080
  41. Caretti G, Di Padova M, Micales B, Lyons GE, Sartorelli V. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 2004;18:2627-38. https://doi.org/10.1101/gad.1241904
  42. Yang Y, Zhou L, Lu L, Wang L, Li X, Jiang P, et al. A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene. 2013;32:3432-42. https://doi.org/10.1038/onc.2012.360
  43. Tong ZT, Cai MY, Wang XG, Kong LL, Mai SJ, Liu YH, et al. EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. 2012;31:583-94. https://doi.org/10.1038/onc.2011.254
  44. Corvetta D, Chayka O, Gherardi S, D'Acunto CW, Cantilena S, Valli E, et al. Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: functional and therapeutic implications. J Biol Chem. 2013;288:8332-41. https://doi.org/10.1074/jbc.M113.454280
  45. Mukhopadhyay NK, Kim J, You S, Morello M, Hager MH, Huang WC, et al. Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2. Oncogene. 2014;33:3235-45. https://doi.org/10.1038/onc.2013.294
  46. Boulay G, Dubuissez M, Van Rechem C, Forget A, Helin K, Ayrault O, et al. Hypermethylated in cancer 1 (HIC1) recruits polycomb repressive complex 2 (PRC2) to a subset of its target genes through interaction with human polycomb-like (hPCL) proteins. J Biol Chem. 2012;287:10509-24. https://doi.org/10.1074/jbc.M111.320234
  47. Hwang-Verslues WW, Chang PH, Jeng YM, Kuo WH, Chiang PH, Chang YC, et al. Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proc Natl Acad Sci U S A. 2013;110:12331-6. https://doi.org/10.1073/pnas.1222684110
  48. Zhang H, Niu B, Hu JF, Ge S, Wang H, Li T, et al. Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II. J Cell Biol. 2011;193:475-87. https://doi.org/10.1083/jcb.201101021
  49. Leseva M, Santostefano KE, Rosenbluth AL, Hamazaki T, Terada N. E2f6-mediated repression of the meiotic Stag3 and Smc1beta genes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b. Epigenetics. 2013;8:873-84. https://doi.org/10.4161/epi.25522
  50. Cakouros D, Isenmann S, Cooper L, Zannettino A, Anderson P, Glackin C, et al. Twist-1 induces Ezh2 recruitment regulating histone methylation along the Ink4A/Arf locus in mesenchymal stem cells. Mol Cell Biol. 2012;32:1433-41. https://doi.org/10.1128/MCB.06315-11
  51. Ciavatta DJ, Yang J, Preston GA, Badhwar AK, Xiao H, Hewins P, et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest. 2010;120:3209-19. https://doi.org/10.1172/JCI40034
  52. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071-6. https://doi.org/10.1038/nature08975
  53. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, et al. Long noncoding RNA HOTAIR regulates polycombdependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71:6320-6. https://doi.org/10.1158/0008-5472.CAN-11-1021
  54. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616-25. https://doi.org/10.1038/onc.2012.193
  55. Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W, et al. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One. 2013;8:e77293. https://doi.org/10.1371/journal.pone.0077293
  56. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689-93. https://doi.org/10.1126/science.1192002
  57. Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011;54:1679-89. https://doi.org/10.1002/hep.24563
  58. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011;29:742-9. https://doi.org/10.1038/nbt.1914
  59. Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 2013;333:213-21. https://doi.org/10.1016/j.canlet.2013.01.033
  60. He W, Cai Q, Sun F, Zhong G, Wang P, Liu H, et al. linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. Biochim Biophys Acta. 2013;1832:1528-37. https://doi.org/10.1016/j.bbadis.2013.05.010
  61. Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322:750-6. https://doi.org/10.1126/science.1163045
  62. Rapicavoli NA, Poth EM, Zhu H, Blackshaw S. The long noncoding RNA Six3OS acts in trans to regulate retinal development by modulating Six3 activity. Neural Dev. 2011;6:32. https://doi.org/10.1186/1749-8104-6-32
  63. Li Q, Su Z, Xu X, Liu G, Song X, Wang R, et al. AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans. Proc Natl Acad Sci U S A. 2012;109:14110-5. https://doi.org/10.1073/pnas.1116597109
  64. Zhu L, Xu PC. Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem Biophys Res Commun. 2013;432:612-7. https://doi.org/10.1016/j.bbrc.2013.02.036
  65. Kaneko S, Bonasio R, Saldana-Meyer R, Yoshida T, Son J, Nishino K, et al. Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin. Mol Cell. 2014;53:290-300. https://doi.org/10.1016/j.molcel.2013.11.012
  66. Kim DH, Saetrom P, Snove O Jr, Rossi JJ. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc Natl Acad Sci U S A. 2008;105:16230-5. https://doi.org/10.1073/pnas.0808830105
  67. Guil S, Soler M, Portela A, Carrere J, Fonalleras E, Gomez A, et al. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol. 2012;19:664-70. https://doi.org/10.1038/nsmb.2315
  68. Wang L, Zeng X, Chen S, Ding L, Zhong J, Zhao JC, et al. BRCA1 is a negative modulator of the PRC2 complex. EMBO J. 2013;32:1584-97. https://doi.org/10.1038/emboj.2013.95
  69. Kaneko S, Li G, Son J, Xu CF, Margueron R, Neubert TA, et al. Phosphorylation of the PRC2 component Ezh2 is cell cycleregulated and up-regulates its binding to ncRNA. Genes Dev. 2010;24:2615-20. https://doi.org/10.1101/gad.1983810
  70. da Rocha ST, Boeva V, Escamilla-Del-Arenal M, Ancelin K, Granier C, Matias NR, et al. Jarid2 is implicated in the initial Xist-induced targeting of PRC2 to the inactive X chromosome. Mol Cell. 2014;53:301-16. https://doi.org/10.1016/j.molcel.2014.01.002
  71. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, et al. Aktmediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science. 2005;310:306-10. https://doi.org/10.1126/science.1118947
  72. Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465-9. https://doi.org/10.1126/science.1227604
  73. Kim E, Kim M, Woo DH, 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. Cancer Cell. 2013;23:839-52. https://doi.org/10.1016/j.ccr.2013.04.008
  74. Sahasrabuddhe AA, Chen X, Chung F, Velusamy T, Lim MS, Elenitoba-Johnson KS. Oncogenic Y641 mutations in EZH2 prevent Jak2/beta-TrCP-mediated degradation. Oncogene. 2014 Jan 27 [Epub]. http://dx.doi.org/10.1038/onc.2013.571.
  75. Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, et al. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 2010;12:1108-14. https://doi.org/10.1038/ncb2116
  76. Wu SC, Zhang Y. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J Biol Chem. 2011;286:28511-9. https://doi.org/10.1074/jbc.M111.240515
  77. Wei Y, Chen YH, Li LY, Lang J, Yeh SP, Shi B, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011;13:87-94. https://doi.org/10.1038/ncb2139
  78. Minnebo N, Gornemann J, O'Connell N, Van Dessel N, Derua R, Vermunt MW, et al. NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes. Nucleic Acids Res. 2013;41:842-54. https://doi.org/10.1093/nar/gks1255
  79. Li J, Hart RP, Mallimo EM, Swerdel MR, Kusnecov AW, Herrup K. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat Neurosci. 2013;16:1745-53. https://doi.org/10.1038/nn.3564
  80. Palacios D, Mozzetta C, Consalvi S, Caretti G, Saccone V, Proserpio V, et al. TNF/p38alpha/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell. 2010;7:455-69. https://doi.org/10.1016/j.stem.2010.08.013
  81. Chu CS, Lo PW, Yeh YH, Hsu PH, Peng SH, Teng YC, et al. O-GlcNAcylation regulates EZH2 protein stability and function. Proc Natl Acad Sci U S A. 2014;111:1355-60. https://doi.org/10.1073/pnas.1323226111
  82. Riising EM, Boggio R, Chiocca S, Helin K, Pasini D. The polycomb repressive complex 2 is a potential target of SUMO modifications. PLoS One. 2008;3:e2704. https://doi.org/10.1371/journal.pone.0002704
  83. Yu YL, Chou RH, Shyu WC, Hsieh SC, Wu CS, Chiang SY, et al. Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke. EMBO Mol Med. 2013;5:531-47. https://doi.org/10.1002/emmm.201201783
  84. Zoabi M, Sadeh R, de Bie P, Marquez VE, Ciechanover A. PRAJA1 is a ubiquitin ligase for the polycomb repressive complex 2 proteins. Biochem Biophys Res Commun. 2011;408:393-8. https://doi.org/10.1016/j.bbrc.2011.04.025
  85. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13:69-80. https://doi.org/10.1016/j.ccr.2007.12.005
  86. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181-5. https://doi.org/10.1038/ng.518
  87. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, 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. Proc Natl Acad Sci U S A. 2010;107:20980-5. https://doi.org/10.1073/pnas.1012525107
  88. Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677-92. https://doi.org/10.1016/j.ccr.2013.04.011
  89. Majer CR, Jin L, Scott MP, Knutson SK, Kuntz KW, Keilhack H, et al. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett. 2012;586:3448-51. https://doi.org/10.1016/j.febslet.2012.07.066
  90. McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012;109:2989-94. https://doi.org/10.1073/pnas.1116418109
  91. Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, et al. Inhibition of PRC2 activity by a gain-offunction H3 mutation found in pediatric glioblastoma. Science. 2013;340:857-61. https://doi.org/10.1126/science.1232245
  92. Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 2013;24:660-72. https://doi.org/10.1016/j.ccr.2013.10.006
  93. Chan KM, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013;27:985-90. https://doi.org/10.1101/gad.217778.113
  94. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268-73.
  95. Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res. 2005;11(24 Pt 1):8570-6. https://doi.org/10.1158/1078-0432.CCR-05-1047
  96. Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 2006;97:484-91. https://doi.org/10.1111/j.1349-7006.2006.00203.x
  97. Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res. 2007;37:974-83. https://doi.org/10.1111/j.1872-034X.2007.00141.x
  98. Ougolkov AV, Bilim VN, Billadeau DD. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res. 2008;14:6790-6. https://doi.org/10.1158/1078-0432.CCR-08-1013
  99. Lee HW, Choe M. Expression of EZH2 in renal cell carcinoma as a novel prognostic marker. Pathol Int. 2012;62:735-41. https://doi.org/10.1111/pin.12001
  100. Rao ZY, Cai MY, Yang GF, He LR, Mai SJ, Hua WF, et al. EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-beta1 and is a predictor of outcome in ovarian carcinoma patients. Carcinogenesis. 2010;31:1576-83. https://doi.org/10.1093/carcin/bgq150
  101. Crea F, Hurt EM, Farrar WL. Clinical significance of Polycomb gene expression in brain tumors. Mol Cancer. 2010;9:265. https://doi.org/10.1186/1476-4598-9-265
  102. Yamada A, Fujii S, Daiko H, Nishimura M, Chiba T, Ochiai A. Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus. Int J Oncol. 2011;38:345-53.
  103. Behrens C, Solis LM, Lin H, Yuan P, Tang X, Kadara H, et al. EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res. 2013;19:6556-65. https://doi.org/10.1158/1078-0432.CCR-12-3946
  104. Alford SH, Toy K, Merajver SD, Kleer CG. Increased risk for distant metastasis in patients with familial early-stage breast cancer and high EZH2 expression. Breast Cancer Res Treat. 2012;132:429-37. https://doi.org/10.1007/s10549-011-1591-2
  105. Crea F, Hurt EM, Mathews LA, Cabarcas SM, Sun L, Marquez VE, et al. Pharmacologic disruption of Polycomb repressive complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer. 2011;10:40. https://doi.org/10.1186/1476-4598-10-40
  106. Gonzalez ME, Moore HM, Li X, Toy KA, Huang W, Sabel MS, et al. EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc Natl Acad Sci U S A. 2014;111:3098-103. https://doi.org/10.1073/pnas.1308953111
  107. Li X, Gonzalez ME, Toy K, Filzen T, Merajver SD, Kleer CG. Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia. Am J Pathol. 2009;175:1246-54. https://doi.org/10.2353/ajpath.2009.090042
  108. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665-7. https://doi.org/10.1038/ng.620
  109. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722-6. https://doi.org/10.1038/ng.621
  110. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med. 2013;210:2627-39. https://doi.org/10.1084/jem.20131144
  111. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 2012;18:298-301. https://doi.org/10.1038/nm.2651
  112. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 2012;26:651-6. https://doi.org/10.1101/gad.186411.111
  113. Mallen-St Clair J, Soydaner-Azeloglu R, Lee KE, Taylor L, Livanos A, Pylayeva-Gupta Y, et al. EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev. 2012;26:439-44. https://doi.org/10.1101/gad.181800.111
  114. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21:525-30. https://doi.org/10.1101/gad.415507
  115. Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su IH, Hannon G, et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136:1122-35. https://doi.org/10.1016/j.cell.2008.12.043
  116. Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, et al. Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem. 2006;281:24790-802. https://doi.org/10.1074/jbc.M604175200
  117. Sasaki M, Yamaguchi J, Itatsu K, Ikeda H, Nakanuma Y. Over-expression of polycomb group protein EZH2 relates to decreased expression of p16 INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol. 2008;215:175-83. https://doi.org/10.1002/path.2345
  118. Wang C, Liu X, Chen Z, Huang H, Jin Y, Kolokythas A, et al. Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma. Mol Carcinog. 2013;52:229-36. https://doi.org/10.1002/mc.21848
  119. Yu H, Simons DL, Segall I, Carcamo-Cavazos V, Schwartz EJ, Yan N, et al. PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ. PLoS One. 2012;7:e51239. https://doi.org/10.1371/journal.pone.0051239
  120. Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells. Cancer Sci. 2008;99:738-46. https://doi.org/10.1111/j.1349-7006.2008.00743.x
  121. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274-84. https://doi.org/10.1038/onc.2008.333
  122. Chen Y, Lin MC, Yao H, Wang H, Zhang AQ, Yu J, et al. Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin. Hepatology. 2007;46:200-8. https://doi.org/10.1002/hep.21668
  123. Cheng AS, Lau SS, Chen Y, Kondo Y, Li MS, Feng H, et al. EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011;71:4028-39. https://doi.org/10.1158/0008-5472.CAN-10-3342
  124. Yang X, Karuturi RK, Sun F, Aau M, Yu K, Shao R, et al. CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PLoS One. 2009;4:e5011. https://doi.org/10.1371/journal.pone.0005011
  125. Guo J, Cai J, Yu L, Tang H, Chen C, Wang Z. EZH2 regulates expression of p57 and contributes to progression of ovarian cancer in vitro and in vivo. Cancer Sci. 2011;102:530-9. https://doi.org/10.1111/j.1349-7006.2010.01836.x
  126. Yu J, Cao Q, Yu J, Wu L, Dallol A, Li J, et al. The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene. 2010;29:5370-80. https://doi.org/10.1038/onc.2010.269
  127. Wu L, Runkle C, Jin HJ, Yu J, Li J, Yang X, et al. CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor. Oncogene. 2014;33:504-13. https://doi.org/10.1038/onc.2012.602
  128. Shin YJ, Kim JH. The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One. 2012;7:e30393. https://doi.org/10.1371/journal.pone.0030393
  129. Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med. 2010;16:286-94. https://doi.org/10.1038/nm.2100
  130. Du J, Li L, Ou Z, Kong C, Zhang Y, Dong Z, et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res Treat. 2012;131:65-73. https://doi.org/10.1007/s10549-011-1396-3
  131. Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, et al. Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med. 2014;6:229ra41. https://doi.org/10.1126/scitranslmed.3008326
  132. Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD, et al. The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia. 2005;7:1011-9. https://doi.org/10.1593/neo.05472
  133. Lu H, Sun J, Wang F, Feng L, Ma Y, Shen Q, et al. Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4. Cell Death Dis. 2013;4:e776. https://doi.org/10.1038/cddis.2013.293
  134. Marchesi I, Fiorentino FP, Rizzolio F, Giordano A, Bagella L. The ablation of EZH2 uncovers its crucial role in rhabdomyosarcoma formation. Cell Cycle. 2012;11:3828-36. https://doi.org/10.4161/cc.22025
  135. Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, et al. EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res. 2012;72:315-24. https://doi.org/10.1158/0008-5472.CAN-11-0961
  136. Fujii S, Ito K, Ito Y, Ochiai A. Enhancer of zeste homologue 2 (EZH2) down-regulates RUNX3 by increasing histone H3 methylation. J Biol Chem. 2008;283:17324-32. https://doi.org/10.1074/jbc.M800224200
  137. Taniguchi H, Jacinto FV, Villanueva A, Fernandez AF, Yamamoto H, Carmona FJ, et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2012;31:1988-94. https://doi.org/10.1038/onc.2011.387
  138. Wu ZL, Zheng SS, Li ZM, Qiao YY, Aau MY, Yu Q. Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell Death Differ. 2010;17:801-10. https://doi.org/10.1038/cdd.2009.162
  139. Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Phar-macologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050-63. https://doi.org/10.1101/gad.1524107
  140. De Carvalho DD, Binato R, Pereira WO, Leroy JM, Colassanti MD, Proto-Siqueira R, et al. BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients. Oncogene. 2011;30:223-33. https://doi.org/10.1038/onc.2010.409
  141. Lu C, Han HD, Mangala LS, Ali-Fehmi R, Newton CS, Ozbun L, et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell. 2010;18:185-97. https://doi.org/10.1016/j.ccr.2010.06.016
  142. Asangani IA, Ateeq B, Cao Q, Dodson L, Pandhi M, Kunju LP, et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol Cell. 2013;49:80-93. https://doi.org/10.1016/j.molcel.2012.10.008
  143. Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, Prensner JR, et al. Coordinated regulation of Polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011;20:187-99. https://doi.org/10.1016/j.ccr.2011.06.016
  144. Shi B, Liang J, Yang X, Wang Y, Zhao Y, Wu H, et al. Integration of estrogen and Wnt signaling circuits by the Polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol. 2007;27:5105-19. https://doi.org/10.1128/MCB.00162-07
  145. Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, et al. PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. Mol Cell. 2013;52:193-205. https://doi.org/10.1016/j.molcel.2013.08.028
  146. Lee ST, Li Z, Wu Z, Aau M, Guan P, Karuturi RK, et al. Context-specific regulation of NF-kappaB target gene expression by EZH2 in breast cancers. Mol Cell. 2011;43:798-810. https://doi.org/10.1016/j.molcel.2011.08.011
  147. Yan J, Ng SB, Tay JL, Lin B, Koh TL, Tan J, et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood. 2013;121:4512-20. https://doi.org/10.1182/blood-2012-08-450494
  148. Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, et al. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012;48:572-86. https://doi.org/10.1016/j.molcel.2012.09.004
  149. He A, Shen X, Ma Q, Cao J, von Gise A, Zhou P, et al. PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev. 2012;26:37-42. https://doi.org/10.1101/gad.173930.111
  150. Su IH, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, Marqueron R, et al. Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell. 2005;121:425-36. https://doi.org/10.1016/j.cell.2005.02.029
  151. Bryant RJ, Winder SJ, Cross SS, Hamdy FC, Cunliffe VT. The Polycomb group protein EZH2 regulates actin polymerization in human prostate cancer cells. Prostate. 2008;68:255-63. https://doi.org/10.1002/pros.20705
  152. Campbell S, Ismail IH, Young LC, Poirier GG, Hendzel MJ. Polycomb repressive complex 2 contributes to DNA doublestrand break repair. Cell Cycle. 2013;12:2675-83. https://doi.org/10.4161/cc.25795
  153. Gonzalez ME, Li X, Toy K, DuPrie M, Ventura AC, Banerjee M, et al. Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1. Oncogene. 2009;28:843-53. https://doi.org/10.1038/onc.2008.433
  154. Gonzalez ME, DuPrie ML, Krueger H, Merajver SD, Ventura AC, Toy KA, et al. Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res. 2011;71:2360-70. https://doi.org/10.1158/0008-5472.CAN-10-1933
  155. Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, et al. BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb repressive complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Res. 2009;11:R63. https://doi.org/10.1186/bcr2354
  156. Alimova I, Venkataraman S, Harris P, Marquez VE, Northcott PA, Dubuc A, et al. Targeting the enhancer of zeste homologue 2 in medulloblastoma. Int J Cancer. 2012;131:1800-9. https://doi.org/10.1002/ijc.27455
  157. Kemp CD, Rao M, Xi S, Inchauste S, Mani H, Fetsch P, et al. Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clin Cancer Res. 2012;18:77-90. https://doi.org/10.1158/1078-0432.CCR-11-0962
  158. Kalushkova A, Fryknas M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, et al. Polycomb target genes are silenced in multiple myeloma. PLoS One. 2010;5:e11483. https://doi.org/10.1371/journal.pone.0011483
  159. Gannon OM, Merida de Long L, Endo-Munoz L, Hazar-Rethinam M, Saunders NA. Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation. Clin Cancer Res. 2013;19:428-41. https://doi.org/10.1158/1078-0432.CCR-12-2505
  160. Fujiwara T, Saitoh H, Inoue A, Kobayashi M, Okitsu Y, Katsuoka Y, et al. 3-Deazaneplanocin A (DZNep), an inhibitor of S-adenosylmethionine-dependent methyltransferase, promotes erythroid differentiation. J Biol Chem. 2014;289:8121-34. https://doi.org/10.1074/jbc.M114.548651
  161. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108-12. https://doi.org/10.1038/nature11606
  162. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8:890-6. https://doi.org/10.1038/nchembio.1084
  163. Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13:842-54. https://doi.org/10.1158/1535-7163.MCT-13-0773
  164. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012;109:21360-5. https://doi.org/10.1073/pnas.1210371110
  165. Hua WF, Fu YS, Liao YJ, Xia WJ, Chen YC, Zeng YX, et al. Curcumin induces down-regulation of EZH2 expression through the MAPK pathway in MDA-MB-435 human breast cancer cells. Eur J Pharmacol. 2010;637:16-21. https://doi.org/10.1016/j.ejphar.2010.03.051
  166. Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, et al. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012;72:335-45. https://doi.org/10.1158/0008-5472.CAN-11-2182
  167. Dimri M, Bommi PV, Sahasrabuddhe AA, Khandekar JD, Dimri GP. Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells. Carcinogenesis. 2010;31:489-95. https://doi.org/10.1093/carcin/bgp305
  168. Wang S, Zhu Y, He H, Liu J, Xu L, Zhang H, et al. Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2. Cancer Sci. 2013;104:750-9. https://doi.org/10.1111/cas.12132
  169. Avan A, Crea F, Paolicchi E, Funel N, Galvani E, Marquez VE, et al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol Cancer Ther. 2012;11:1735-46. https://doi.org/10.1158/1535-7163.MCT-12-0037
  170. Fiskus W, Rao R, Balusu R, Ganguly S, Tao J, Sotomayor E, et al. Superior efficacy of a combined epigenetic therapy against human mantle cell lymphoma cells. Clin Cancer Res. 2012;18:6227-38. https://doi.org/10.1158/1078-0432.CCR-12-0873
  171. Hayden A, Johnson PW, Packham G, Crabb SJ. S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res Treat. 2011;127:109-19. https://doi.org/10.1007/s10549-010-0982-0
  172. Sun F, Chan E, Wu Z, Yang X, Marquez VE, Yu Q. Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells. Mol Cancer Ther. 2009;8:3191-202. https://doi.org/10.1158/1535-7163.MCT-09-0479
  173. Lv Y, Yuan C, Xiao X, Wang X, Ji X, Yu H, et al. The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma. Oncol Rep. 2012;28:147-54.
  174. Hu S, Yu L, Li Z, Shen Y, Wang J, Cai J, et al. Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol Ther. 2010;10:788-95. https://doi.org/10.4161/cbt.10.8.12913

Cited by

  1. Characterization and Pharmacologic Targeting of EZH2, a Fetal Retinal Protein and Epigenetic Regulator, in Human Retinoblastoma vol.95, pp.11, 2014, https://doi.org/10.1038/labinvest.2015.104
  2. Role of the ubiquitin proteasome system in hematologic malignancies vol.263, pp.1, 2014, https://doi.org/10.1111/imr.12236
  3. Small molecule inhibitors of EZH2: the emerging translational landscape vol.7, pp.3, 2014, https://doi.org/10.2217/epi.15.14
  4. siRNA Silencing EZH2 Reverses Cisplatin-resistance of Human Non-small Cell Lung and Gastric Cancer Cells vol.16, pp.6, 2014, https://doi.org/10.7314/apjcp.2015.16.6.2425
  5. Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma vol.5, pp.None, 2014, https://doi.org/10.1038/srep12999
  6. Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma vol.36, pp.3, 2015, https://doi.org/10.1007/s13277-014-2763-6
  7. MiR-101 reverses the hypomethylation of the LMO3 promoter in glioma cells vol.6, pp.10, 2014, https://doi.org/10.18632/oncotarget.3181
  8. H3K27me3 is an Epigenetic Mark of Relevance in Endometriosis vol.22, pp.9, 2014, https://doi.org/10.1177/1933719115578924
  9. Enhancer of zeste acts as a major developmental regulator of Ciona intestinalis embryogenesis vol.4, pp.9, 2015, https://doi.org/10.1242/bio.010835
  10. Overexpression of enhancer of zeste homolog 2 (EZH2) characterizes an aggressive subset of prostate cancers and predicts patient prognosis independently from pre- and postoperatively assessed clinicop vol.36, pp.11, 2014, https://doi.org/10.1093/carcin/bgv137
  11. EZH2 in Bladder Cancer, a Promising Therapeutic Target vol.16, pp.11, 2015, https://doi.org/10.3390/ijms161126000
  12. A Gene Regulatory Program in Human Breast Cancer vol.201, pp.4, 2014, https://doi.org/10.1534/genetics.115.180125
  13. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma vol.104, pp.3, 2014, https://doi.org/10.1007/s12185-016-2048-5
  14. Problems of glioblastoma multiforme drug resistance vol.81, pp.2, 2014, https://doi.org/10.1134/s0006297916020036
  15. GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers vol.7, pp.35, 2014, https://doi.org/10.18632/oncotarget.11008
  16. Proximal and distal regulation of the HYAL1 gene cluster by the estrogen receptor α in breast cancer cells vol.7, pp.47, 2016, https://doi.org/10.18632/oncotarget.12630
  17. The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway vol.7, pp.11, 2014, https://doi.org/10.18632/oncotarget.7260
  18. The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia vol.7, pp.24, 2014, https://doi.org/10.18632/oncotarget.9371
  19. Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential vol.7, pp.25, 2014, https://doi.org/10.18632/oncotarget.9518
  20. Targeting NK Cells for Anticancer Immunotherapy: Clinical and Preclinical Approaches vol.7, pp.None, 2014, https://doi.org/10.3389/fimmu.2016.00152
  21. High EZH2 Protein Expression Is Associated with Poor Overall Survival in Patients with Luminal A Breast Cancer vol.19, pp.1, 2016, https://doi.org/10.4048/jbc.2016.19.1.53
  22. MiR-101 Targets the EZH2/Wnt/β-Catenin the Pathway to Promote the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells vol.6, pp.None, 2014, https://doi.org/10.1038/srep36988
  23. Expression of miRNA-26b in the diagnosis and prognosis of patients with non-small-cell lung cancer vol.12, pp.9, 2016, https://doi.org/10.2217/fon.16.21
  24. Expression Profile and Function Analysis of LncRNAs during Priming Phase of Rat Liver Regeneration vol.11, pp.6, 2016, https://doi.org/10.1371/journal.pone.0156128
  25. DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity vol.7, pp.7, 2014, https://doi.org/10.1038/cddis.2016.198
  26. DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity vol.7, pp.7, 2014, https://doi.org/10.1038/cddis.2016.198
  27. Identification of Polycomb Group Protein EZH2-Mediated DNA Mismatch Repair Gene MSH2 in Human Uterine Fibroids vol.23, pp.10, 2016, https://doi.org/10.1177/1933719116638186
  28. Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer vol.11, pp.10, 2016, https://doi.org/10.1371/journal.pone.0165005
  29. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selecti vol.59, pp.21, 2016, https://doi.org/10.1021/acs.jmedchem.6b01315
  30. EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells vol.7, pp.11, 2014, https://doi.org/10.1038/cddis.2016.383
  31. The Ezh2 polycomb group protein drives an aggressive phenotype in melanoma cancer stem cells and is a target of diet derived sulforaphane vol.55, pp.12, 2016, https://doi.org/10.1002/mc.22448
  32. Significance of EZH2 expression in canine mammary tumors vol.12, pp.None, 2014, https://doi.org/10.1186/s12917-016-0789-2
  33. High EZH2 expression is correlated to metastatic disease in pediatric soft tissue sarcomas vol.16, pp.None, 2016, https://doi.org/10.1186/s12935-016-0338-x
  34. Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report vol.11, pp.1, 2016, https://doi.org/10.1186/s13000-016-0588-x
  35. Regulation of cancer epigenomes with a histone-binding synthetic transcription factor vol.2, pp.None, 2017, https://doi.org/10.1038/s41525-016-0002-3
  36. Morphoproteomics, E6/E7 in-situ hybridization, and biomedical analytics define the etiopathogenesis of HPV-associated oropharyngeal carcinoma and provide targeted therapeutic options vol.46, pp.46, 2014, https://doi.org/10.1186/s40463-017-0230-2
  37. EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis vol.8, pp.8, 2014, https://doi.org/10.18632/oncotarget.14586
  38. Methylation-mediated silencing of microRNA-211 promotes cell growth and epithelial to mesenchymal transition through activation of the AKT/β-catenin pathway in GBM vol.8, pp.15, 2017, https://doi.org/10.18632/oncotarget.15531
  39. Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells vol.8, pp.24, 2014, https://doi.org/10.18632/oncotarget.16314
  40. Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo vol.10, pp.None, 2014, https://doi.org/10.2147/ott.s134784
  41. Decreased expression of JMJD3 predicts poor prognosis of patients with clear cell renal cell carcinoma vol.14, pp.2, 2014, https://doi.org/10.3892/ol.2017.6362
  42. SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer vol.36, pp.10, 2014, https://doi.org/10.1038/onc.2016.300
  43. Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3 vol.12, pp.4, 2014, https://doi.org/10.1371/journal.pone.0174775
  44. Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression vol.18, pp.2, 2014, https://doi.org/10.2174/1389202917666160803165229
  45. miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer vol.15, pp.8, 2017, https://doi.org/10.1158/1541-7786.mcr-16-0327
  46. Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors vol.12, pp.8, 2014, https://doi.org/10.1371/journal.pone.0183155
  47. Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation : Impact on Regulation of Notch Pathway vol.187, pp.10, 2014, https://doi.org/10.1016/j.ajpath.2017.06.014
  48. TET-Mediated Sequestration of miR-26 Drives EZH2 Expression and Gastric Carcinogenesis vol.77, pp.22, 2014, https://doi.org/10.1158/0008-5472.can-16-2964
  49. Interplay of DNA methyltransferase 1 and EZH2 through inactivation of Stat3 contributes to β-elemene-inhibited growth of nasopharyngeal carcinoma cells vol.7, pp.None, 2017, https://doi.org/10.1038/s41598-017-00626-6
  50. The role of EZH2 in overall survival of colorectal cancer: a meta-analysis vol.7, pp.None, 2014, https://doi.org/10.1038/s41598-017-13670-z
  51. Identification of coexistence of BRAF V600E mutation and EZH2 gain specifically in melanoma as a promising target for combination therapy vol.15, pp.None, 2014, https://doi.org/10.1186/s12967-017-1344-z
  52. Metastatic biomarkers in synovial sarcoma vol.5, pp.1, 2014, https://doi.org/10.1186/s40364-017-0083-x
  53. DUXAP8 , a pseudogene derived lncRNA, promotes growth of pancreatic carcinoma cells by epigenetically silencing CDKN1A and KLF2 vol.38, pp.None, 2014, https://doi.org/10.1186/s40880-018-0333-9
  54. MET/ERK and MET/JNK Pathway Activation Is Involved in BCR-ABL Inhibitor-resistance in Chronic Myeloid Leukemia vol.138, pp.12, 2018, https://doi.org/10.1248/yakushi.18-00142
  55. Effects of Enhancer of Zeste Homolog 2 (EZH2) Expression on Brain Glioma Cell Proliferation and Tumorigenesis vol.24, pp.None, 2018, https://doi.org/10.12659/msm.909814
  56. Emerging roles of Myc in stem cell biology and novel tumor therapies vol.37, pp.1, 2014, https://doi.org/10.1186/s13046-018-0835-y
  57. EZH2, HIF-1, and Their Inhibitors: An Overview on Pediatric Cancers vol.6, pp.None, 2014, https://doi.org/10.3389/fped.2018.00328
  58. EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer vol.37, pp.2, 2014, https://doi.org/10.1038/onc.2017.311
  59. Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA vol.9, pp.2, 2014, https://doi.org/10.1038/s41419-017-0224-z
  60. Long noncoding RNA GAS5 promotes bladder cancer cells apoptosis through inhibiting EZH2 transcription vol.9, pp.2, 2014, https://doi.org/10.1038/s41419-018-0264-z
  61. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy vol.61, pp.3, 2014, https://doi.org/10.1021/acs.jmedchem.7b01375
  62. EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes vol.9, pp.31, 2018, https://doi.org/10.18632/oncotarget.25128
  63. Impact of OGT deregulation on EZH2 target genes FOXA1 and FOXC1 expression in breast cancer cells vol.13, pp.6, 2014, https://doi.org/10.1371/journal.pone.0198351
  64. Epigenetic silencing of tumor suppressor gene CDKN1A by oncogenic long non-coding RNA SNHG1 in cholangiocarcinoma vol.9, pp.7, 2014, https://doi.org/10.1038/s41419-018-0768-6
  65. Epigenetic dysregulation of key developmental genes in radiation‐induced rat mammary carcinomas vol.143, pp.2, 2014, https://doi.org/10.1002/ijc.31309
  66. The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma vol.233, pp.9, 2014, https://doi.org/10.1002/jcp.26545
  67. Long noncoding RNA PCAT6 functions as an oncogene by binding to EZH2 and suppressing LATS2 in non-small-cell lung cancer vol.37, pp.None, 2014, https://doi.org/10.1016/j.ebiom.2018.10.004
  68. The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p vol.17, pp.1, 2014, https://doi.org/10.1186/s12943-018-0894-x
  69. Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2 vol.92, pp.24, 2018, https://doi.org/10.1128/jvi.00909-18
  70. Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival vol.9, pp.None, 2019, https://doi.org/10.1038/s41598-019-39122-4
  71. Aberrant differential expression of EZH2 and H3K27me3 in extranodal NK/T-cell lymphoma, nasal type, is associated with disease progression and prognosis vol.83, pp.None, 2014, https://doi.org/10.1016/j.humpath.2018.08.025
  72. Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators vol.20, pp.6, 2014, https://doi.org/10.2174/1389202920666191017163837
  73. Epigenetics of Bladder Cancer: Where Biomarkers and Therapeutic Targets Meet vol.10, pp.None, 2014, https://doi.org/10.3389/fgene.2019.01125
  74. Long noncoding RNA TALNEC2 plays an oncogenic role in breast cancer by binding to EZH2 to target p57KIP2 and involving in p‐p38 MAPK and NF‐κB pathways vol.120, pp.3, 2019, https://doi.org/10.1002/jcb.27680
  75. iPS-Cell Technology and the Problem of Genetic Instability—Can It Ever Be Safe for Clinical Use? vol.8, pp.3, 2014, https://doi.org/10.3390/jcm8030288
  76. New directions in treating peripheral T-cell lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination vol.12, pp.3, 2014, https://doi.org/10.1080/17474086.2019.1583102
  77. Stratifying nonfunctional pituitary adenomas into two groups distinguished by macrophage subtypes vol.10, pp.22, 2014, https://doi.org/10.18632/oncotarget.26775
  78. Prolactin Receptor Signaling Regulates a Pregnancy-Specific Transcriptional Program in Mouse Islets vol.160, pp.5, 2014, https://doi.org/10.1210/en.2018-00991
  79. Protein dynamics analysis reveals that missense mutations in cancer‐related genes appear frequently on hinge‐neighboring residues vol.87, pp.6, 2014, https://doi.org/10.1002/prot.25673
  80. Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit Is Required for Uterine Epithelial Integrity vol.189, pp.6, 2014, https://doi.org/10.1016/j.ajpath.2019.02.016
  81. Silencing of microRNA-708 promotes cell growth and epithelial-to-mesenchymal transition by activating the SPHK2/AKT/β-catenin pathway in glioma vol.10, pp.6, 2014, https://doi.org/10.1038/s41419-019-1671-5
  82. DZNep-mediated apoptosis in B-cell lymphoma is independent of the lymphoma type, EZH2 mutation status and MYC, BCL2 or BCL6 translocations vol.14, pp.8, 2014, https://doi.org/10.1371/journal.pone.0220681
  83. Interaction of EZH2 and P65 is involved in the arsenic trioxide-induced anti-angiogenesis in human triple-negative breast cancer cells vol.35, pp.4, 2019, https://doi.org/10.1007/s10565-018-09458-0
  84. Current state of melanoma diagnosis and treatment vol.20, pp.11, 2019, https://doi.org/10.1080/15384047.2019.1640032
  85. EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive chronic lymphocytic leukaemia vol.14, pp.11, 2019, https://doi.org/10.1080/15592294.2019.1633867
  86. Long non‐coding small nucleolar RNA host genes in digestive cancers vol.8, pp.18, 2014, https://doi.org/10.1002/cam4.2622
  87. Targeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation vol.10, pp.1, 2014, https://doi.org/10.1038/s41467-019-10176-2
  88. Cigarette smoke affects the onco-suppressor DAB2IP expression in bronchial epithelial cells of COPD patients vol.9, pp.1, 2014, https://doi.org/10.1038/s41598-019-52179-5
  89. HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia vol.17, pp.1, 2014, https://doi.org/10.1186/s12967-019-2115-9
  90. lncRNA SNHG6 regulates EZH2 expression by sponging miR-26a/b and miR-214 in colorectal cancer vol.12, pp.1, 2014, https://doi.org/10.1186/s13045-018-0690-5
  91. MicroRNA-33b Suppresses Epithelial–Mesenchymal Transition Repressing the MYC–EZH2 Pathway in HER2+ Breast Carcinoma vol.10, pp.None, 2014, https://doi.org/10.3389/fonc.2020.01661
  92. Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis vol.250, pp.1, 2014, https://doi.org/10.1002/path.5352
  93. Exosome-Delivered LncHEIH Promotes Gastric Cancer Progression by Upregulating EZH2 and Stimulating Methylation of the GSDME Promoter vol.8, pp.None, 2014, https://doi.org/10.3389/fcell.2020.571297
  94. Network-Based Genetic Profiling Reveals Cellular Pathway Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma vol.17, pp.4, 2014, https://doi.org/10.3390/ijerph17041373
  95. A TGF-β-MTA1-SOX4-EZH2 signaling axis drives epithelial-mesenchymal transition in tumor metastasis vol.39, pp.10, 2014, https://doi.org/10.1038/s41388-019-1132-8
  96. LncRNA-ANCR down-regulation suppresses invasion and migration of colorectal cancer cells by regulating EZH2 expression vol.18, pp.1, 2014, https://doi.org/10.3233/cbm-161715
  97. HOXC10 promotes cell migration, invasion, and tumor growth in gastric carcinoma cells through upregulating proinflammatory cytokines vol.235, pp.4, 2020, https://doi.org/10.1002/jcp.29246
  98. Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway vol.27, pp.6, 2014, https://doi.org/10.1038/s41417-019-0117-7
  99. Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time vol.11, pp.6, 2014, https://doi.org/10.1021/acsmedchemlett.0c00045
  100. Long noncoding RNA ANRIL promotes the malignant progression of cholangiocarcinoma by epigenetically repressing ERRFI1 expression vol.111, pp.7, 2020, https://doi.org/10.1111/cas.14447
  101. The EZH2–PHACTR2–AS1–Ribosome Axis induces Genomic Instability and Promotes Growth and Metastasis in Breast Cancer vol.80, pp.13, 2014, https://doi.org/10.1158/0008-5472.can-19-3326
  102. Genomic profiling in renal cell carcinoma vol.16, pp.8, 2014, https://doi.org/10.1038/s41581-020-0301-x
  103. INI-1 (SMARCB1)-Deficient Undifferentiated Sinonasal Carcinoma: Novel Paradigm of Molecular Testing in the Diagnosis and Management of Sinonasal Malignancies vol.25, pp.9, 2014, https://doi.org/10.1634/theoncologist.2019-0830
  104. The Roles of the Histone Protein Modifier EZH2 in the Uterus and Placenta vol.4, pp.3, 2014, https://doi.org/10.3390/epigenomes4030020
  105. The long non‐coding RNA SNHG1 promotes bladder cancer progression by interacting with miR‐143‐3p and EZH2 vol.24, pp.20, 2014, https://doi.org/10.1111/jcmm.15806
  106. Forkhead Box C1 (FOXC1) Expression in Stromal Cells within the Microenvironment of T and NK Cell Lymphomas: Association with Tumor Dormancy and Activation vol.52, pp.4, 2014, https://doi.org/10.4143/crt.2020.032
  107. EZH2 overexpression dampens tumor-suppressive signals via an EGR1 silencer to drive breast tumorigenesis vol.39, pp.48, 2014, https://doi.org/10.1038/s41388-020-01484-9
  108. Inhibition of EZH2 Enhances the Antitumor Efficacy of Metformin in Prostate Cancer vol.19, pp.12, 2014, https://doi.org/10.1158/1535-7163.mct-19-0874
  109. Acquired resistance to DZNep-mediated apoptosis is associated with copy number gains of AHCY in a B-cell lymphoma model vol.20, pp.1, 2014, https://doi.org/10.1186/s12885-020-06937-8
  110. Elevated expression of RUNX3 co-expressing with EZH2 in esophageal cancer patients from India vol.20, pp.None, 2014, https://doi.org/10.1186/s12935-020-01534-y
  111. FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway vol.12, pp.1, 2014, https://doi.org/10.1186/s13073-020-00773-y
  112. Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness vol.12, pp.12, 2014, https://doi.org/10.3390/cancers12123716
  113. Taxanes in cancer treatment: Activity, chemoresistance and its overcoming vol.54, pp.None, 2021, https://doi.org/10.1016/j.drup.2020.100742
  114. The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review vol.9, pp.None, 2021, https://doi.org/10.3389/fcell.2021.683254
  115. Dynamic‐shared Pharmacophore Approach as Tool to Design New Allosteric PRC2 Inhibitors, Targeting EED Binding Pocket vol.40, pp.2, 2014, https://doi.org/10.1002/minf.202000148
  116. MicroRNAs Involved in Inflammatory Breast Cancer: Oncogene and Tumor Suppressors with Possible Targets vol.40, pp.3, 2014, https://doi.org/10.1089/dna.2020.6320
  117. Elevated EZH2 in ischemic heart disease epigenetically mediates suppression of NaV1.5 expression vol.153, pp.None, 2021, https://doi.org/10.1016/j.yjmcc.2020.12.012
  118. The noncanonical role of EZH2 in cancer vol.112, pp.4, 2014, https://doi.org/10.1111/cas.14840
  119. Clinical and Genomic Characteristics of Adult Diffuse Midline Glioma vol.53, pp.2, 2014, https://doi.org/10.4143/crt.2020.694
  120. Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer vol.13, pp.11, 2014, https://doi.org/10.3390/cancers13112719
  121. Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation vol.82, pp.6, 2014, https://doi.org/10.1002/ddr.21796
  122. Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas vol.64, pp.20, 2014, https://doi.org/10.1021/acs.jmedchem.1c01154
  123. EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma vol.11, pp.1, 2021, https://doi.org/10.1038/s41598-021-00889-0