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Department of Surgery, Section of Urology, University of Wisconsin Medical School [D. F. J., Y. S., N. N., C. S., D. H., H. K.], Environmental Toxicology [D. F. J.], and University of Wisconsin Comprehensive Cancer Center [D. F. J., L. F. M., C. C.], Madison, Wisconsin 53792, and the Oncology Center [J. G. H.] and Brady Urological Institute [W. B. I.], Johns Hopkins Hospital, Baltimore, Maryland 21287
Androgen-independent metastatic prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. In this study, we evaluate DNA hypermethylation as a potential transcriptional regulatory mechanism in AR-negative prostate cancer cell lines. Nucleotide sequence analysis demonstrates a 
1.5-kb CpG island in the AR gene that encompasses the transcription start site and exon 1. Using Southern blotting with methylation-sensitive restriction enzymes and methylation-specific PCR, we find aberrant methylation in the AR expression-negative cell lines Du145, DuPro, TSU-PR1, and PPC1. Incomplete methylation in the AR CpG island is also seen in normal female breast and ovarian tissues consistent with the inactivation of one X chromosome by hypermethylation. In contrast, prostate cancer cell lines LNCaP and PC3 express AR and are unmethylated. Normal prostate epithelial cell strains demonstrate no methylation. Exposure of AR-negative prostate cancer cell lines to 5-aza-2' deoxycytidine, a demethylating agent, induces the reexpression of AR RNA in DuPro and TSU-PR1. This reexpression is associated with a demethylation of this region. Prostate-specific antigen, an androgen-responsive gene, is also specifically induced in these lines after AR reexpression. Therefore, in vitro DNA methylation of the 5' CpG AR island may be associated with the loss of AR expression. Furthermore, our results demonstrate that treatment with demethylating agents may engender the reexpression and function of the androgen receptor in AR-negative cell lines.
1 This work was supported in part by Grant CA76184 from the NIH and the Howard Hughes Medical Research Resources grant to the University of Wisconsin School of Medicine.
2 To whom requests for reprints should be addressed, at K6/527 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. Phone: (608) 265-8828; Fax: (608) 265-8133; E-mail: jarrard@surgery.wisc.edu.
Received 8/ 3/98. Accepted 10/14/98.
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