Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling1, that the polycomb group protein enhancer of zeste homolog 2 (EZH2)2,3 is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes4 targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
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This study was made possible by tissues donated by patients with metastatic prostate cancer enrolled in the University of Michigan, Rapid Autopsy Program funded by the Specialized Program of Research Excellence (SPORE) in Prostate Cancer at the National Cancer Institute. We thank J. Wei for clinical data collection; K. Hamer for preparing polycomb antibodies; R. Kunkel for figure preparation; J. Harwood and M. LeBlanc for technical assistance; A. Menon for sequence verification; and C. Ingold and G. Tueckmantel for database assistance. A.M.C. is a Pew Foundation Scholar. This work is supported in part by grants from the NIH (A.M.C.), CaPCURE (A.M.C.) and the Michigan SPORE in Prostate Cancer (K.P., M.A.R., A.M.C. and M.G.S.).
The authors declare that they have no competing financial interests.
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Varambally, S., Dhanasekaran, S., Zhou, M. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002). https://doi.org/10.1038/nature01075
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