The enhancer of zeste homolog 2 gene contributes to cell proliferation and apoptosis resistance in renal cell carcinoma cells
Nina Wagener
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorDaniela Holland
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorJulia Bulkescher
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorIrena Crnković-Mertens
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorKarin Hoppe-Seyler
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorHanswalter Zentgraf
German Cancer Research Center, Electron Microscopy (F090), Heidelberg, Germany
Search for more papers by this authorMaria Pritsch
Department of Medical Biometry, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorStephan Buse
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorJesco Pfitzenmaier
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorAxel Haferkamp
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorMarkus Hohenfellner
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Felix Hoppe-Seyler
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Fax: +49-6221-424852
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Im Neuenheimer Feld 242, 69120 Heidelberg, GermanySearch for more papers by this authorNina Wagener
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorDaniela Holland
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorJulia Bulkescher
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorIrena Crnković-Mertens
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorKarin Hoppe-Seyler
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Search for more papers by this authorHanswalter Zentgraf
German Cancer Research Center, Electron Microscopy (F090), Heidelberg, Germany
Search for more papers by this authorMaria Pritsch
Department of Medical Biometry, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorStephan Buse
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorJesco Pfitzenmaier
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorAxel Haferkamp
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorMarkus Hohenfellner
Department of Urology, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Felix Hoppe-Seyler
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Heidelberg, Germany
Fax: +49-6221-424852
German Cancer Research Center, Molecular Therapy of Virus-Associated Cancers (F065), Im Neuenheimer Feld 242, 69120 Heidelberg, GermanySearch for more papers by this authorAbstract
The enhancer of zeste homolog 2 (EZH2) gene has been recently linked to human malignancies where it may serve as a new target for cancer therapy. Here, we analyzed EZH2 expression in primary renal cell carcinoma (RCC) specimens and in nontumorous tissue samples from adult kidney. EZH2 transcripts were detectable in all RCC specimens examined. Expression levels were significantly higher in tumor tissue (p ≤ 0.0001) than in samples from normal adult kidney. Moreover, inhibition of endogenous EZH2 expression in RCC cell lines by RNA interference (RNAi) led to reduced proliferation and increased apoptosis in RCC cells. These data show that EZH2 is overexpressed in RCC. Furthermore, they indicate that the EZH2 gene plays a role for both the proliferation and the apoptosis resistance of RCC cells. Targeted inhibition of EZH2 could therefore represent a novel strategy to improve the therapeutic response of RCC. © 2008 Wiley-Liss, Inc.
References
- 1 Jemal A,Siegel R,Ward E,Murray T,Xu J,Thun MJ. Cancer statistics, 2007. Cancer J Clin 2007; 57: 43–66.
- 2 Flanigan RC,Campbell SC,Clark JI,Picken MM. Metastatic renal cell carcinoma. Curr Treat Options Oncol 2003; 4: 385–90.
- 3 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: 1039–43.
- 4 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: 185–96.
- 5 Kuzmichev A,Nishioka K,Erdjument-Bromage H,Tempst P,Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Zeste protein. Genes Dev 2002; 16: 2893–905.
- 6 Vire E,Brenner C,Deplus R,Blanchon L,Fraga M,Didelot C,Morey L,Van Eynde A,Bernard D,Vanderwinden JM,Bollen M,Esteller M, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439: 871–4.
- 7 Jacobs JJ,van Lohuizen M. Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta 2002; 1602: 151–61.
- 8 Cao R,Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Gen Dev 2004; 14: 155–64.
- 9 Varambally S,Dhanasekaran SM,Zhou M,Barrette TR,Kumar-Sinha C,Sanda MG,Ghosh D,Pienta KJ,Sewalt RG,Otte AP,Rubin MA,Chinnaiyan AM. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 419: 624–9.
- 10 Bachmann IM,Halvorsen OJ,Collett K,Stefansson IM,Straume O,Haukaas SA,Salvesen HB,Otte AP,Akslen LA. 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.
- 11 Kleer CG,Cao Q,Varambally S,Shen R,Ota I,Tomlins SA,Ghosh D,Sewalt RG,Otte AP,Hayes DF,Sabel MS,Livant D, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 2003; 100: 11606–11.
- 12 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.
- 13 Visser HP,Gunster MJ,Kluin-Nelemans HC,Manders EM,Raaphorst FM,Meijer CJ,Willemze R,Otte AP. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br J Haematol 2001; 112: 950–8.
- 14 Croonquist PA,Van Ness B. The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype. Oncogene 2005; 24: 6269–80.
- 15 Tang X,Milyavsky M,Shats I,Erez N,Goldfinger N,Rotter V. Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene 2004; 23: 5759–69.
- 16 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: 1886–901.
- 17 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: 1050–63.
- 18 Crnkovic-Mertens I,Muley T,Meister M,Hartenstein B,Semzow J,Butz K,Hoppe-Seyler F. The anti-apoptotic livin gene is an important determinant for the apoptotic resistance of non-small cell lung cancer cells. Lung Cancer 2006; 54: 135–42.
- 19 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. Br J Cancer 2005; 92: 1754–8.
- 20 Livak KJ,Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402–8.
- 21 Vogt M,Butz K,Dymalla S,Semzow J,Hoppe-Seyler F. Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein. Oncogene 2006; 25: 4009–15.
- 22 Fox MH. A model for the computer analysis of synchronous DNA distributions obtained by flow cytometry. Cytometry 1980; 1: 71–7.
- 23 Epping MT,Wang L,Edel MJ,Carlee L,Hernandez M,Bernards R. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell 2005; 122: 835–47.
- 24 Shi B,Liang J,Yang X,Wang Y,Zhao Y,Wu H,Sun L,Zhang Y,Chen Y,Li R,Zhang Y,Hong M, 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.
- 25 Bracken AP,Dietrich N,Pasini D,Hansen KH,Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 2006; 20: 1123–36.
- 26 Kotake Y,Cao R,Viatour P,Sage J,Zhang Y,Xiong Y. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4α tumor suppressor gene. Genes Dev 2007; 21: 49–54.
- 27 Ding L,Kleer CG. Enhancer of zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res 2006; 66: 9352–5.
- 28 Collett K,Eide GE,Arnes J,Stefansson IM,Eide J,Braaten A,Aas T,Otte AP,Akslen LA. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res 2006; 12: 1168–74.
- 29 Chen Y,Lin MC,Yao H,Wang H,Zhang AQ,Yu J,Hui CK,Lau GK,He ML,Sung J,Kung HF. Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin. Hepatology 2007; 46: 200–8.
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