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Methylation of the 5' CpG Island of the Endothelin B Receptor Gene Is Common in Human Prostate Cancer¹

James Buchanan Brady Urological Institute Research Laboratories [J. B. N., W-H. L., S. H. N., D. F. J., J. D. B., W. G. N., G. S. B.], Johns Hopkins Oncology Center [W. G. N.], Johns Hopkins Hospital, Baltimore, Maryland 21287-2411, and Abbott Laboratories, Abbott Park, Illinois 60064-3500 [S. R. M., T. J. O.]

Production of the potent vasoconstrictor endothelin-1 (ET-1) by human prostate cancer cells accompanies prostate cancer progression in vivo. The predominant endothelin receptor expressed by normal prostate epithelium, ET_B, is not expressed by any of the established human prostate cancer cell lines, and ET_B binding is decreased on prostate cancer tissues. ET_B, which may mediate ET-1 clearance and may inhibit ET-1 secretion, is encoded by a gene that contains a 5' CpG island encompassing the transcriptional regulatory region. We examined this regulatory region of the ET_B receptor gene (EDNRB) to determine whether hypermethylation of cytidine nucleotides accompanies decreased ET_B expression in human prostate cancer. We found somatic methylation of CpG island sequences in EDNRB in 5 of 5 human prostate cancer cell lines, 15 of 21 primary prostate cancer tissues, and 8 of 14 prostate cancer metastases (70% of samples overall). Normal tissues contained only unmethylated EDNRB. Treatment of human prostatic carcinoma cell line cultures with 5-azacytidine induced ET_B mRNA expression, suggesting that CpG island methylation changes might accompany the apparent transcriptional silencing of EDNRB in vivo.

¹ This work was supported by a grant from the American Foundation of Urologic Disease, Inc. (to J. B. N., a Dornier Scholar), NIH Prostate Cancer Specialized Programs of Research Excellence CA 58236, and CaP CURE.

² To whom requests for reprints should be addressed, at James Buchanan Brady Urological Institute, Department of Urology, A344, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224.

Received 9/18/96. Accepted 11/18/96.

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