1. ¹Second Department of Pathology, Mie University School of Medicine, Mie, Japan
2. ²Department of Urology, Chiba University School of Medicine, Chiba, Japan
3. ³The Johns Hopkins Oncology Center, Baltimore, Maryland
4. ⁴Department of Urology, Kanazawa University School of Medicine, Kanazawa, Japan

Correspondence: Dr. Masatoshi Watanabe, Second Department of Pathology, Mie University School of Medicine, 2-174 Edobashi, Tsu-shi, Mie 514, Japan. Fax: 81 59 231 5310; E-mail: mawata@doc.medic.mie-u.ac.jp

Received 2 June 2000.

Abstract

Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. Heterogenous expression of androgen receptor (AR), which appears to be related to variable responses to endocrine therapy in prostate cancer (PCa) may also be due to epigenetic factors. The methylation status of the 5' CpG island 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 DU145, CpG-rich regions of the AR were hypermethylated. By an immunohistochemical analysis, only one PCa sample had no AR expression, the others being heterogenous. Bisulfite sequencing and methylation-specific PCR analysis showed aberrant methylation of AR 5'-regulatory region in 20% of 10 primary and 28% of 14 hormone-refractory PCa samples. To clarify the effect of epigenetic regulation on AR expression, we treated three prostate cancer cell lines with a demethylating agent, 5-aza-2'-deoxycytidine (azaC), and a histone deacetylase inhibitor, Trichostatin A (TSA). In DU145, re-expression of AR mRNA was detected after treatment with azaC and/or TSA. Our results suggest that epigenetic regulations including CpG methylation and histone acetylation may play important roles in the regulation of the AR.