Epigenetic regulation of androgen receptor gene expression in human prostate cancers

Epigenetic mechanisms including DNA methylation and histone deacetylation a re thought to play important roles in gene transcriptional inactivation. He terogenous expression of androgen receptor (AR), which appears to be relate d to variable responses to endocrine therapy in prostate cancer (PCa) may a lso be due to epigenetic factors. The methylation status of the 5' CpG isla nd of the AR in 3 prostate cancer cell lines and 10 primary and 14 hormone- refractory PCa samples was determined using the bisulfite PCR methods. In D U145, CpG-rich regions of the AW were hypermethylated. By an immunohistoche mical analysis, only one PCa sample had no AR expression, the others being heterogenous. Bisulfite sequencing and methylation-specific PCR analysis sh owed aberrant methylation of AR 5'-regulatory region in 20% of 10 primary a nd 28% of 14 hormone-refractory PCa samples. To clarify the effect of epige netic regulation on AR expression, we treated three prostate cancer cell li nes with a demethylating agent, 5-aza-2'-deoxycytidine (azaC), and a histon e deacetylase inhibitor, Trichostatin A (TSA). In DU145, re-expression of A R mRNA was detected after treatment with azaC and/or TSA. Our results sugge st that epigenetic regulations including CpG methylation and histone acetyl ation may play important roles in the regulation of the AR.