Epigenetic changes have been recently recognized as important in human cancers. Enhancer of zeste homologue 2 gene (EZH2) has been shown the overexpression in various human cancers, consistent with a straightforward role of EZH2 as an oncogene, but its function in carcinogenesis is partly contradictory. The role of EZH2 in development of human colorectal cancer (CRC) has not yet been clarified. In the present study, we observed up-regulation of EZH2 expression in tumor tissues from CRC patients. The expression of EZH2 in CRC cell lines is consistent with the trend in cancer tissues using reverse transcription polymerase chain reaction (RT-PCR). We showed that TNM stage and lymph node metastasis in CRC patients are significantly correlated with EZH2 expression levels. EZH2 level of transcription and protein is inhibited by small interfering RNA (siRNA). More importantly, EZH2-siRNA inhibits the proliferation and migration of SW620 cells while promoting their apoptosis, and inducing G0/G1 cell cycle arrest of SW620 cells. Collectively, our results suggest that upregulated EZH2 expression may contribute to the progression of the patients with CRC. A comprehensive study of epigenetic mechanisms and the relevance of EZH2 in CRC is important for fully understanding this disease and as a basis for developing new treatment options in patients with CRC.
WeinstockBWardSCHarpazNWarnerRRItzkowitzSKimMK. Clinical and prognostic features of rectal neuroendocrine tumors. Neuroendocrinology2013; 98: 180–7.
4.
Wan D, Gu W, Xu G, Shen C, Ding D, Shen S, Wang S, Gong X, He S, Zhi Q. Effects of common polymorphisms rs2910164 in miR-146a and rs11614913 in miR-196a2 on susceptibility to colorectal cancer: A systematic review meta-analysis. Clin Transl Oncol. Epub ahead of print 8 January 2014, DOI:10.1007/s12094-013-1150-x.
5.
DawsonMAKouzaridesT. Cancer epigenetics: From mechanism to therapy. Cell2012; 150: 12–27.
6.
HeSXieFLiuYTongQMochizukiKLapinskiPEManiRSReddyPMochizukiIChinnaiyanAMMineishiSKingPDZhangY. The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. Blood2013; 122: 4119–28.
7.
KleerCGCaoQVaramballySShenROtaITomlinsSAGhoshDSewaltRGOtteAPHayesDFSabelMSLivantDWeissSJRubinMAChinnaiyanAM. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA2003; 100: 11606–11.
8.
VaramballySDhanasekaranSMZhouMBarretteTRKumar-SinhaCSandaMGGhoshDPientaKJSewaltRGOtteAPRubinMAChinnaiyanAM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature2002; 419: 624–9.
9.
OugolkovAVBilimVNBilladeauDD. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res2008; 14: 6790–6.
10.
WagenerNHollandDBulkescherJCrnković-MertensIHoppe-SeylerKZentgrafHPritschMBuseSPfitzenmaierJHaferkampAHohenfellnerMHoppe-SeylerF. The enhancer of zeste homolog 2 gene contributes to cell proliferation and apoptosis resistance in renal cell carcinoma cells. Int J Cancer2008; 123: 1545–50.
11.
RamanJDMonganNPTickooSKBoorjianSAScherrDSGudasLJ. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res2005; 11: 8570–6.
12.
WatanabeHSoejimaKYasudaHKawadaINakachiIYodaSNaokiKIshizakaA. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int2008; 8: 15–15.
13.
TanJYangXZhuangLJiangXChenWLeePLKaruturiRKTanPBLiuETYuQ. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev2007; 21: 1050–63.
14.
LuCHanHDMangalaLSAli-FehmiRNewtonCSOzbunLArmaiz-PenaGNHuWStoneRLMunkarahARavooriMKShahzadMMLeeJWMoraELangleyRRCarrollARMatsuoKSpannuthWASchmandtRJenningsNBGoodmanBWJaffeRBNickAMKimHSGuvenEOChenYHLiLYHsuMCColemanRLCalinGADenkbasEBLimJYLeeJSKundraVBirrerMJHungMCLopez-BeresteinGSoodAK. Regulation of tumor angiogenesis by EZH2. Cancer Cell2010; 18: 185–97.
15.
FussbroichBWagenerNMacher-GoeppingerSBennerAFälthMSültmannHHolzerAHoppe-SeylerKHoppe-SeylerF. EZH2 depletion blocks the proliferation of colon cancer cells. PLoS One2011; 6: e21651–e21651.
16.
RaoZYCaiMYYangGFHeLRMaiSJHuaWFLiaoYJDengHXChenYCGuanXYZengYXKungHFXieD. EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-beta1 and is a predictor of outcome in ovarian carcinoma patients. Carcinogenesis2010; 31: 1576–83.
17.
MinJZaslavskyAFedeleGMcLaughlinSKReczekEEDe RaedtTGuneyIStrochlicDEMacconaillLEBeroukhimRBronsonRTRyeomSHahnWCLodaMCichowskiK. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med2010; 16: 286–94.
18.
TaniguchiHJacintoFVVillanuevaAFernandezAFYamamotoHCarmonaFJPuertasSMarquezVEShinomuraYImaiKEstellerM. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene2012; 31: 1988–94.
19.
MorinRDJohnsonNASeversonTMMungallAJAnJGoyaRPaulJEBoyleMWoolcockBWKuchenbauerFYapDHumphriesRKGriffithOLShahSZhuHKimbaraMShashkinPCharlotJFTcherpakovMCorbettRTamAVarholRSmailusDMoksaMZhaoYDelaneyAQianHBirolIScheinJMooreRHoltRHorsmanDEConnorsJMJonesSAparicioSHirstMGascoyneRDMarraMA. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet2010; 42: 181–5.
20.
KodachLLJacobsRJHeijmansJvan NoeselCJLangersAMVerspagetHWHommesDWOfferhausGJvan den BrinkGRHardwickJC. The role of EZH2 and DNA methylation in the silencing of the tumour suppressor RUNX3 in colorectal cancer. Carcinogenesis2010; 31: 1567–75.
21.
He S, Zhou H, Zhu X, Hu S, Fei M, Wan D, Gu W, Yang X, Shi D, Zhou J, Zhou J, Zhu Z, Wang L, Li D, Zhang Y. Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance. Biomed Pharmacother 2014;68:507–13.
22.
He SB, Zhao H, Fei M, Wu YG, Wang L, Zhu XG, Li DC. Expression of co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro. Oncol Rep 2012;28:262–8.
23.
Liu PF, Wu YY, Hu Y, Wang L, He SB, Zhu YB, Zhu XG. PAUF silencing by RNA interference inhibit the malignant phenotypes in human colorectal cancer cell. Oncol Rep 2013;30:213–20.
24.
He S, Yuan Y, Wang L, Yu M, Zhu Y, Zhu X. Effects of cyclin-dependent kinase 8 specific siRNA on the proliferation and apoptosis of colon cancer cells. J Exp Clin Cancer Res 2011;30:109.
25.
Zheng J, Li Y, Yang J, Liu Q, Shi M, Zhang R, Shi H, Ren Q, Ma J, Guo H, Tao Y, Xue Y, Jiang N, Yao L, Liu W. NDRG2 inhibits hepatocellular carcinoma adhesion, migration and invasion by regulating CD24 expression. BMC Cancer 2011;11:1–9.
26.
Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 2008;647:21–9.
27.
Arakawa T, Masaki T, Hirai T, Doi S, Kuratsune M, Arihiro K, Kohno N, Yorioka N. Activation of signal transducer and activator of transcription 3 correlates with cell proliferation and renal injury in human glomerulonephritis. Nephrol Dial Transplant 2008;23:3418–26.
28.
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;345–53.
29.
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-b-catenin signaling. Cancer Cell 2011;19:86–100.
30.
Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res 2011;17:2613–18.
31.
Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S, Boucher G, Chagnon P, Drouin S, Lambert R, Rondeau C, Bilodeau A, Lavallée S, Sauvageau M, Hébert J, Sauvageau G. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 2012;26:651–6.
32.
Hock H. A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev 2012;26:751–5.
33.
Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 1998;8:324–30.
34.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR. International Vidaza High-Risk MDS, Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223–32.
35.
Ghadjar P, Coupland SE, Na IK, Noutsias M, Letsch A, Stroux A, Bauer S, Buhr HJ, Thiel E, Scheibenbogen C, Keilholz U. Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol 2006;24:1910–6.
36.
Chiba T, Suzuki E, NegishiM, Saraya A,Miyagi S, Konuma T, Tanaka S, Tada M, Kanai F, Imazeki F, Iwama A, Yokosuka O. 3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells. Int J Cancer 2012;130:2557–67.
37.
Tan J, Yang X, Zhuang L, Jiang X, ChenW, 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;21:1050–63.
38.
Lotze MT, Maranchie J, Appleman L. Inhibiting antophagy: a novel approach for the treatment of renal cell cancinoma. Cancer 2013;341–7.
39.
Zheng HY, Zhang XY, Wang XF, Sun BC. Autophagy enhances the aggressiveness of human colorectal cancer cells and their ability to adapt to apptotic stimulus. Cacer Biol Med 2012;9:105–10.
40.
Gu W, Wan DW, Qian QY, Yi B, Gu YL, He ZL, Wang L, He SB. Ambra1 is an essential regulator of autophagy and apoptosis in SW620 cells: Prosurvival role of Ambra1. Plos One 2014;9:e90151.
41.
Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008;322:1695–9.
42.
Wan DW, He SB, Xie BH, Xu GH, Gu W, Shen CL, Hu Y, Wang Xinsheng, Zhi QM, Wang L. Aberrant expression of miR-199a-3p and its clinical significance in colorectal cancers. Med Oncol 2013;30:378.
43.
Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q, Chen YC, Peng Y, Yao KT, Kung HF, Li XP. MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res 2011;71:225–33.
