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 profiling, 
that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is 
overexpressed in hormone-refractory, metastatic prostate cancer. Small 
interfering RNA (siRNA) duplexes 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.