Abstract
Abstract
Prostate cancer is the most common cancer in American men and acquisition of androgen independence by prostate cancer is the key problem causing prostate cancer progression to highly aggressive form of cancer, leaving limited modalities in its treatment. Recent studies suggest that G protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to development of androgen independence. We previously reported that RGS2, an inhibitor of GPCR signaling, inhibits androgen-independent AR activation in prostate cancer cells (Cao et al., (2006) Oncogene, 25: 3719-3734). Here, we report that RGS2 protein expression was significantly reduced in human prostate cancer specimens compared to adjacent normal prostate tissues. Interestingly, RGS2 repression in androgen-independent prostate cancer cells and human prostate cancer specimens is not simply due to the loss of the RGS2 gene. Instead, methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the RGS2 gene promoter correlates with RGS2 down-regulation in prostate cancer cells and human prostate cancer specimens. Hypermethylation of the RGS2 gene promoter abolished its promoter activity and suppressed RGS2 gene expression. Conversely, the DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine induced re-expression of RGS2 in androgen-independent prostate cancer cells via demethylation of the RGS2 promoter to inhibit androgen-independent prostate cancer growth. Furthermore, ectopic re-expression of RGS2 in androgen-independent prostate cancer cells by RGS2-adenovirus infection suppressed tumorigenicity and growth of xenografts in castrated nude mice. Taken together, our results suggest that RGS2 repression due to hypermethylation of its promoter could unmask a latent pathway for AR activation by various GPCRs, thus contributing to prostate cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1710.