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5‐aza‐2′‐deoxycytidine suppresses androgen independent prostate cancer growth by restoring RGS2 expression
Author(s) -
Wolff Dennis W.,
Xie Yan,
Gatalica Zoran,
Yang Mingjie,
Wang Bo,
Wang Jincheng,
Lin MingFong,
Abel Peter W.,
Tu Yaping
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.802.6
Subject(s) - rgs2 , androgen receptor , prostate cancer , cancer research , dna methylation , methylation , biology , chemistry , cancer , microbiology and biotechnology , gene expression , signal transduction , g protein , gene , genetics , gtpase activating protein
G‐protein coupled receptor (GPCR)‐stimulated androgen‐independent activation of androgen receptor (AR) contributes to prostate cancer progression to a highly aggressive and hormone‐refractory phenotype. We previously reported that RGS2, an inhibitor of GPCRs, inhibits androgen‐independent AR activation. Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent non‐cancerous tissues. Methylation‐specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 down‐regulation in prostate cancer. In vitro methylation of this promoter also suppressed RGS2 expression. Conversely, reversal of RGS2 promoter methylation with 5‐aza‐2′‐deoxycytidine (5‐Aza‐dC) induced RGS2 re‐expression in androgen‐independent prostate cancer cells and inhibited their growth under androgen‐deficient conditions. Interestingly, the inhibitory effect of 5‐Aza‐dC was significantly reduced by an RGS2‐targeted short hairpin RNA, indicating that re‐expressed RGS2 contributed to this growth inhibition. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation by GPCRs. Targeting this reversible process may provide a novel strategy for suppressing prostate cancer progression. Supported by NIH (CA125661, 88184) and DOD W81XWH‐07‐1‐0189.