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. 2013 Apr 30;4(5):331–341. doi: 10.1007/s13238-013-2093-2

EZH2, an epigenetic driver of prostate cancer

Yeqing Angela Yang 1, Jindan Yu 1,2,✉
PMCID: PMC4131440  NIHMSID: NIHMS608132  PMID: 23636686

Abstract

The histone methyltransferase EZH2 has been in the limelight of the field of cancer epigenetics for a decade now since it was first discovered to exhibit an elevated expression in metastatic prostate cancer. It persists to attract much scientific attention due to its important role in the process of cancer development and its potential of being an effective therapeutic target. Thus here we review the dysregulation of EZH2 in prostate cancer, its function, upstream regulators, downstream effectors, and current status of EZH2-targeting approaches. This review therefore provides a comprehensive overview of EZH2 in the context of prostate cancer.

Keywords: EZH2, histone methyltransferase, prostate cancer, epigenetics

References

  1. Arisan S, Buyuktuncer ED, Palavan-Unsal N, Caskurlu T, Cakir OO, Ergenekon E. Increased expression of EZH2, a polycomb group protein, in bladder carcinoma. Urol Int. 2005;75:252–257. doi: 10.1159/000087804. [DOI] [PubMed] [Google Scholar]
  2. Beke L, Nuytten M, Van Eynde A, Beullens M, Bollen M. The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. Oncogene. 2007;26:4590–4595. doi: 10.1038/sj.onc.1210248. [DOI] [PubMed] [Google Scholar]
  3. Berezovska OP, Glinskii AB, Yang Z, Li XM, Hoffman RM, Glinsky GV. Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle. 2006;5:1886–1901. doi: 10.4161/cc.5.16.3222. [DOI] [PubMed] [Google Scholar]
  4. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002;168:2439–2443. doi: 10.1016/S0022-5347(05)64163-8. [DOI] [PubMed] [Google Scholar]
  5. Bhalla KN. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol. 2005;23:3971–3993. doi: 10.1200/JCO.2005.16.600. [DOI] [PubMed] [Google Scholar]
  6. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;441:349–353. doi: 10.1038/nature04733. [DOI] [PubMed] [Google Scholar]
  7. 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;22:5323–5335. doi: 10.1093/emboj/cdg542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitroand in vivo. Cancer Res. 2000;60:5165–5170. [PubMed] [Google Scholar]
  9. Cao P, Deng Z, Wan M, Huang W, Cramer SD, Xu J, Lei M, Sui G. MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta. Mol Cancer. 2010;9:108. doi: 10.1186/1476-4598-9-108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, Prensner JR, Kim JH, Brenner JC, Jing X, Cao X, et al. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011;20:187–199. doi: 10.1016/j.ccr.2011.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, Mehra R, Laxman B, Cao X, Yu J, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274–7284. doi: 10.1038/onc.2008.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–1043. doi: 10.1126/science.1076997. [DOI] [PubMed] [Google Scholar]
  13. 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;18:2627–2638. doi: 10.1101/gad.1241904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Center, M., Siegel, R., and Ahmedin, J. (2011). Global Cancer Facts & Figures 2nd Edition, A.C. Society, ed. (Atlanta, American Cancer Society).
  15. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, Ping B, Otte AP, Hung MC. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science. 2005;310:306–310. doi: 10.1126/science.1118947. [DOI] [PubMed] [Google Scholar]
  16. Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN, Hung MC. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell. 2011;19:86–100. doi: 10.1016/j.ccr.2010.10.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chang FR, Hwang TL, Yang YL, Li CE, Wu CC, Issa HH, Hsieh WB, Wu YC. Anti-inflammatory and cytotoxic diterpenes from formosan Polyalthia longifolia var. pendula. Planta Med. 2006;72:1344–1347. doi: 10.1055/s-2006-951691. [DOI] [PubMed] [Google Scholar]
  18. Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas-Tikhonenko A, Mendell JT. Widespread microRNA repression by Myc contributes to tumorigenesis. Nature Genet. 2008;40:43–50. doi: 10.1038/ng.2007.30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Research. 2011;17:2613–2618. doi: 10.1158/1078-0432.CCR-10-2156. [DOI] [PubMed] [Google Scholar]
  20. Chen H, Tu SW, Hsieh JT. Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J Biol Chem. 2005;280:22437–22444. doi: 10.1074/jbc.M501379200. [DOI] [PubMed] [Google Scholar]
  21. Christman JK. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21:5483–5495. doi: 10.1038/sj.onc.1205699. [DOI] [PubMed] [Google Scholar]
  22. Coulombe RA, Jr., Sharma RP, Huggins JW. Pharmacokinetics of the antiviral agent 3-deazaneplanocin A. Eur J Drug Metab Pharmacokinet. 1995;20:197–202. doi: 10.1007/BF03189670. [DOI] [PubMed] [Google Scholar]
  23. Crea F, Hurt EM, Mathews LA, Cabarcas SM, Sun L, Marquez VE, Danesi R, Farrar WL. Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer. 2011;10:40. doi: 10.1186/1476-4598-10-40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002;111:185–196. doi: 10.1016/s0092-8674(02)00975-3. [DOI] [PubMed] [Google Scholar]
  25. Dang CV, O’Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target gene network. Semin Cancer Biol. 2006;16:253–264. doi: 10.1016/j.semcancer.2006.07.014. [DOI] [PubMed] [Google Scholar]
  26. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nature reviews. Cancer. 2002;2:389–396. doi: 10.1038/nrc801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Diaz, E., Machutta, C.A., Chen, S., Jiang, Y., Nixon, C., Hofmann, G., Key, D., Sweitzer, S., Patel, M., Wu, Z., et al. (2012). Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens. J Biomol Screen 17. 1279-1292. [DOI] [PubMed]
  28. Drach J, Lopez-Berestein G, McQueen T, Andreeff M, Mehta K. Induction of differentiation in myeloid leukemia cell lines and acute promyelocytic leukemia cells by liposomal all-transretinoic acid. Cancer Res. 1993;53:2100–2104. [PubMed] [Google Scholar]
  29. Du J, Li L, Ou Z, Kong C, Zhang Y, Dong Z, Zhu S, Jiang H, Shao Z, Huang B, et al. FOXC1, a target of polycomb, inhibits metastasis of breast cancer cells. Breast Cancer Res Treat. 2012;131:65–73. doi: 10.1007/s10549-011-1396-3. [DOI] [PubMed] [Google Scholar]
  30. Enokida H, Shiina H, Urakami S, Igawa M, Ogishima T, Li LC, Kawahara M, Nakagawa M, Kane CJ, Carroll PR, et al. Multigene methylation analysis for detection and staging of prostate cancer. Clinical Cancer Res. 2005;11:6582–6588. doi: 10.1158/1078-0432.CCR-05-0658. [DOI] [PubMed] [Google Scholar]
  31. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917. doi: 10.1002/ijc.25516. [DOI] [PubMed] [Google Scholar]
  32. Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H, Tanaka A, Komatsu Y, Nishino N, Yoshida M, et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer research. 2002;62:4916–4921. [PubMed] [Google Scholar]
  33. Gibbons RJ. Histone modifying and chromatin remodelling enzymes in cancer and dysplastic syndromes. Human Mol Genet. 2005;14(Spec1):R85–92. doi: 10.1093/hmg/ddi106. [DOI] [PubMed] [Google Scholar]
  34. Glazer RI, Hartman KD, Knode MC, Richard MM, Chiang PK, Tseng CK, Marquez VE. 3-Deazaneplanocin: a new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60. Biochem Biophys Res Commun. 1986;135:688–694. doi: 10.1016/0006-291x(86)90048-3. [DOI] [PubMed] [Google Scholar]
  35. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–1076. doi: 10.1038/nature08975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hagiwara Y, Kasukabe T, Kaneko Y, Niitsu N, Okabe-Kado J. Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells. Int J Hemat. 2010;92:136–143. doi: 10.1007/s12185-010-0627-4. [DOI] [PubMed] [Google Scholar]
  37. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670–3679. doi: 10.1002/cncr.24429. [DOI] [PubMed] [Google Scholar]
  38. Hoang TC, Bui TK, Taguchi T, Watanabe T, Sato Y. All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein. J Eep Clin Cancer Res. 2010;29:165. doi: 10.1186/1756-9966-29-165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Hoffmann MJ, Engers R, Florl AR, Otte AP, Muller M, Schulz WA. Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer. Cancer Biolo Ther. 2007;6:1403–1412. doi: 10.4161/cbt.6.9.4542. [DOI] [PubMed] [Google Scholar]
  40. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, Ruhl L, Tatalovich Z, Cho H, et al. SEER Cancer Statistics Review, 1975–2009. 2011. [Google Scholar]
  41. Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, Caragacianu D, Schrump DS. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res. 2009;69:3570–3578. doi: 10.1158/0008-5472.CAN-08-2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Eng J Med. 2010;363:411–422. doi: 10.1056/NEJMoa1001294. [DOI] [PubMed] [Google Scholar]
  43. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:1099–1105. doi: 10.1200/JCO.2009.25.0597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Kerppola TK. Polycomb group complexes—many combinations, many functions. Trends Cell Biol. 2009;19:692–704. doi: 10.1016/j.tcb.2009.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003;100:11606–11611. doi: 10.1073/pnas.1933744100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Knudsen BS, Vasioukhin V. Mechanisms of prostate cancer initiation and progression. Adv Cancer Res. 2010;109:1–50. doi: 10.1016/B978-0-12-380890-5.00001-6. [DOI] [PubMed] [Google Scholar]
  47. 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;2:669–683. doi: 10.18632/oncotarget.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, Li Y, Ali S, Sethi S, Hassan O, et al. Loss of let-7 upregulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PloS One. 2012;7:e33729. doi: 10.1371/journal.pone.0033729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Kumar-Sinha C, Tomlins SA, Chinnaiyan AM. Recurrent gene fusions in prostate cancer. Nature reviews. Cancer. 2008;8:497–511. doi: 10.1038/nrc2402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Lai MT, Yang CC, Lin TY, Tsai FJ, Chen WC. Depsipeptide (FK228) inhibits growth of human prostate cancer cells. Urol Oncol. 2008;26:182–189. doi: 10.1016/j.urolonc.2007.01.020. [DOI] [PubMed] [Google Scholar]
  51. Landeira D, Fisher AG. Inactive yet indispensable: the tale of Jarid2. Trends Cell Biol. 2011;21:74–80. doi: 10.1016/j.tcb.2010.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Lassi K, Dawson NA. Emerging therapies in castrateresistant prostate cancer. Curr Opinion Oncol. 2009;21:260–265. doi: 10.1097/CCO.0b013e32832a1868. [DOI] [PubMed] [Google Scholar]
  53. Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, Kotliarova S, Kotliarov Y, Walling J, Ahn S, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13:69–80. doi: 10.1016/j.ccr.2007.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125:301–313. doi: 10.1016/j.cell.2006.02.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Leeb M, Pasini D, Novatchkova M, Jaritz M, Helin K, Wutz A. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 2010;24:265–276. doi: 10.1101/gad.544410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Li LC, Okino ST, Dahiya R. DNA methylation in prostate cancer. Biochim Biophys Acta. 2004;1704:87–102. doi: 10.1016/j.bbcan.2004.06.001. [DOI] [PubMed] [Google Scholar]
  57. Lin YH, Lee CC, Chang FR, Chang WH, Wu YC, Chang JG. 16-hydroxycleroda-3,13-dien-15,16-olide regulates the expression of histone-modifying enzymes PRC2 complex and induces apoptosis in CML K562 cells. Life Sci. 2011;89:886–895. doi: 10.1016/j.lfs.2011.09.011. [DOI] [PubMed] [Google Scholar]
  58. Liu Z, Ren G, Shangguan C, Guo L, Dong Z, Li Y, Zhang W, Zhao L, Hou P, Zhang Y, et al. ATRA inhibits the proliferation of DU145 prostate cancer cells through reducing the methylation level of HOXB13 gene. PloS One. 2012;7:e40943. doi: 10.1371/journal.pone.0040943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Lu C, Han HD, Mangala LS, Ali-Fehmi R, Newton CS, Ozbun L, Armaiz-Pena GN, Hu W, Stone RL, Munkarah A, et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell. 2010;18:185–197. doi: 10.1016/j.ccr.2010.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838. doi: 10.1038/nature03702. [DOI] [PubMed] [Google Scholar]
  61. 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;97:484–491. doi: 10.1111/j.1349-7006.2006.00203.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Iii AD, Diaz E, et al. Nature. 2012. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. [DOI] [PubMed] [Google Scholar]
  63. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nature Rev Cancer. 2008;8:976–990. doi: 10.1038/nrc2231. [DOI] [PubMed] [Google Scholar]
  64. Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, Guney I, Strochlic DE, Macconaill LE, Beroukhim R, et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nature Med. 2010;16:286–294. doi: 10.1038/nm.2100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Morey L, Helin K. Polycomb group protein-mediated repression of transcription. Trends Bio Sci. 2010;35:323–332. doi: 10.1016/j.tibs.2010.02.009. [DOI] [PubMed] [Google Scholar]
  66. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature genetics. 2010;42:181–185. doi: 10.1038/ng.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, Miller EL, O’Connor MB, Kingston RE, Simon JA. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002;111:197–208. doi: 10.1016/s0092-8674(02)00976-5. [DOI] [PubMed] [Google Scholar]
  68. Nelson WG, De Marzo AM, Yegnasubramanian S. Epigenetic alterations in human prostate cancers. Endocrinology. 2009;150:3991–4002. doi: 10.1210/en.2009-0573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27:1788–1793. doi: 10.1038/sj.onc.1210809. [DOI] [PubMed] [Google Scholar]
  70. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12:1665–1671. doi: 10.1158/1078-0432.CCR-06-0067. [DOI] [PubMed] [Google Scholar]
  71. Pietersen AM, van Lohuizen M. Stem cell regulation by polycomb repressors: postponing commitment. Current opinion in cell biology. 2008;20:201–207. doi: 10.1016/j.ceb.2008.01.004. [DOI] [PubMed] [Google Scholar]
  72. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67:6130–6135. doi: 10.1158/0008-5472.CAN-07-0533. [DOI] [PubMed] [Google Scholar]
  73. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nature Biotech. 2011;29:742–749. doi: 10.1038/nbt.1914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. 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;11:8570–8576. doi: 10.1158/1078-0432.CCR-05-1047. [DOI] [PubMed] [Google Scholar]
  75. Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000;406:593–599. doi: 10.1038/35020506. [DOI] [PubMed] [Google Scholar]
  76. Ren G, Baritaki S, Marathe H, Feng J, Park S, Beach S, Bazeley PS, Beshir AB, Fenteany G, Mehra R, et al. Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res. 2012;72:3091–3104. doi: 10.1158/0008-5472.CAN-11-3546. [DOI] [PubMed] [Google Scholar]
  77. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129:1311–1323. doi: 10.1016/j.cell.2007.05.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Saramaki OR, Tammela TL, Martikainen PM, Vessella RL, Visakorpi T. The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer. Genes Chrom Cancer. 2006;45:639–645. doi: 10.1002/gcc.20327. [DOI] [PubMed] [Google Scholar]
  79. Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010;7:299–313. doi: 10.1016/j.stem.2010.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Schulz WA, Hoffmann MJ. Epigenetic mechanisms in the biology of prostate cancer. Semin Cancer Biol. 2009;19:172–180. doi: 10.1016/j.semcancer.2009.02.006. [DOI] [PubMed] [Google Scholar]
  81. Shapiro D, Tareen B. Current and emerging treatments in the management of castration-resistant prostate cancer. Exp Rev Anticancer. 2012;12:951–964. doi: 10.1586/era.12.59. [DOI] [PubMed] [Google Scholar]
  82. 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. doi: 10.1371/journal.pone.0030393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Simon JA, Tamkun JW. Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes. Curr Opin Genet Dev. 2002;12:210–218. doi: 10.1016/s0959-437x(02)00288-5. [DOI] [PubMed] [Google Scholar]
  84. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. 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;107:20980–20985. doi: 10.1073/pnas.1012525107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nature Rev Cancer. 2006;6:846–856. doi: 10.1038/nrc1991. [DOI] [PubMed] [Google Scholar]
  86. Squazzo SL, O’Geen H, Komashko VM, Krig SR, Jin VX, Jang SW, Margueron R, Reinberg D, Green R, Farnham PJ. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 2006;16:890–900. doi: 10.1101/gr.5306606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–45. doi: 10.1038/47412. [DOI] [PubMed] [Google Scholar]
  88. Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, Wakiyama S, Fujita H, Shirouzu K, Mori M. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Brit J Cancer. 2005;92:1754–1758. doi: 10.1038/sj.bjc.6602531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Sun F, Li J, Yu Q, Chan E. Loading 3-deazaneplanocin A into pegylated unilamellar liposomes by forming transient phenylboronic acid-drug complex and its pharmacokinetic features in Sprague-Dawley rats. Europ J Pharm Biopharm. 2012;80:323–331. doi: 10.1016/j.ejpb.2011.10.014. [DOI] [PubMed] [Google Scholar]
  90. Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–1063. doi: 10.1101/gad.1524107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Tang X, Milyavsky M, Shats I, Erez N, Goldfinger N, Rotter V. Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene. 2004;23:5759–5769. doi: 10.1038/sj.onc.1207706. [DOI] [PubMed] [Google Scholar]
  92. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–693. doi: 10.1126/science.1192002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. van der Vlag J, Otte AP. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nature Genet. 1999;23:474–478. doi: 10.1038/70602. [DOI] [PubMed] [Google Scholar]
  94. Van Dessel N, Beke L, Gornemann J, Minnebo N, Beullens M, Tanuma N, Shima H, Van Eynde A, Bollen M. The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets. Nucleic Acids Res. 2010;38:7500–7512. doi: 10.1093/nar/gkq643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695–1699. doi: 10.1126/science.1165395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–629. doi: 10.1038/nature01075. [DOI] [PubMed] [Google Scholar]
  97. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–874. doi: 10.1038/nature04431. [DOI] [PubMed] [Google Scholar]
  98. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al. A micro-RNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–2261. doi: 10.1073/pnas.0510565103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y. Role of histone H2A ubiquitination in Polycomb silencing. Nature. 2004;431:873–878. doi: 10.1038/nature02985. [DOI] [PubMed] [Google Scholar]
  100. Watanabe H, Soejima K, Yasuda H, Kawada I, Nakachi I, Yoda S, Naoki K, Ishizaka A. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell international. 2008;8:15. doi: 10.1186/1475-2867-8-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, Krause H. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med. 2005;16:349–353. [PubMed] [Google Scholar]
  102. Wilkinson FH, Park K, Atchison ML. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc Natl Acad Sci U S A. 2006;103:19296–19301. doi: 10.1073/pnas.0603564103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007;26:5541–5552. doi: 10.1038/sj.onc.1210620. [DOI] [PubMed] [Google Scholar]
  104. Yegnasubramanian S, Kowalski J, Gonzalgo ML, Zahurak M, Piantadosi S, Walsh PC, Bova GS, De Marzo AM, Isaacs WB, Nelson WG. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res. 2004;64:1975–1986. doi: 10.1158/0008-5472.can-03-3972. [DOI] [PubMed] [Google Scholar]
  105. Yu J, Cao Q, Mehra R, Laxman B, Yu J, Tomlins SA, Creighton CJ, Dhanasekaran SM, Shen R, Chen G, et al. Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer. Cancer Cell. 2007;12:419–431. doi: 10.1016/j.ccr.2007.10.016. [DOI] [PubMed] [Google Scholar]
  106. Yu J, Cao Q, Yu J, Wu L, Dallol A, Li J, Chen G, Grasso C, Cao X, Lonigro RJ, et al. The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene. 2010;29:5370–5380. doi: 10.1038/onc.2010.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 2010;17:443–454. doi: 10.1016/j.ccr.2010.03.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Yu J, Yu J, Rhodes DR, Tomlins SA, Cao X, Chen G, Mehra R, Wang X, Ghosh D, Shah RB, et al. A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer research. 2007;67:10657–10663. doi: 10.1158/0008-5472.CAN-07-2498. [DOI] [PubMed] [Google Scholar]
  109. Zhang XK. Vitamin A and apoptosis in prostate cancer. Endocr Relat Cancer. 2002;9:87–102. doi: 10.1677/erc.0.0090087. [DOI] [PubMed] [Google Scholar]
  110. Zhao JC, Yu J, Runkle C, Wu L, Hu M, Wu D, Liu JS, Wang Q, Qin ZS, Yu J. Cooperation between Polycomb and androgen receptor during oncogenic transformation. Genome Res. 2012;22:322–331. doi: 10.1101/gr.131508.111. [DOI] [PMC free article] [PubMed] [Google Scholar]

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