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We previously reported that regulator of G\u2010protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen\u2010independent AR activation (Cao et al., <jats:italic>Oncogene<\/jats:italic> 2006;25:3719\u201034). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation\u2010specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. <jats:italic>In vitro<\/jats:italic> methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5\u2010aza\u20102\u2032\u2010deoxycytidine (5\u2010Aza\u2010dC) induced RGS2 reexpression in androgen\u2010independent prostate cancer cells and inhibited their growth under androgen\u2010deficient conditions. Interestingly, the inhibitory effect of 5\u2010Aza\u2010dC was significantly reduced by an RGS2\u2010targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen\u2010independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity.<\/jats:p>","DOI":"10.1002\/ijc.26138","type":"journal-article","created":{"date-parts":[[2011,4,16]],"date-time":"2011-04-16T03:28:25Z","timestamp":1302924505000},"page":"1521-1531","source":"Crossref","is-referenced-by-count":41,"title":["Epigenetic repression of regulator of G\u2010protein signaling 2 promotes androgen\u2010independent prostate cancer cell growth"],"prefix":"10.1002","volume":"130","author":[{"given":"Dennis 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