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Epigenetic Inactivation of the Dioxin-Responsive Cytochrome P4501A1 Gene in Human Prostate Cancer

¹ Department of Urology, San Francisco Veterans Affairs Medical Center and the University of California at San Francisco, San Francisco, California and ² Department of Urology, School of Medicine, Shimane University, Izumo, Shimane, Japan

Requests for reprints: Steven T. Okino, Department of Urology, San Francisco Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Phone: 415-221-4810, ext. 3509; Fax: 415-750-6639; E-mail steveokino{at}gmail.com.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is a toxic environmental contaminant that works through dioxin response elements (DRE) to activate gene expression. We tested the hypothesis that cancer-related epigenetic changes suppress dioxin activation of the cytochrome P4501A1 (CYP1A1) gene. 5-Aza-2'-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation, increases TCDD-inducible CYP1A1 mRNA expression in cancerous LNCaP cells but not in noncancerous PWR-1E and RWPE-1 cells (all human prostate cell lines). Bisulfite DNA sequencing shows that the TCDD-responsive CYP1A1 enhancer is highly methylated in LNCaP cells but not in RWPE-1 cells. In vivo footprinting experiments reveal that unmethylated DRE sites do not bind protein in response to TCDD in LNCaP cells, whereas inducible DRE occupancy occurs in RWPE-1 cells. Pretreatment of LNCaP cells with 5-aza-CdR partially restores TCDD-inducible DRE occupancy, showing that DNA methylation indirectly suppresses DRE occupancy. Chromatin immunoprecipitation experiments reveal that LNCaP cells lack trimethyl histone H3 lysine 4, a mark of active genes, on the CYP1A1 regulatory region, whereas this histone modification is prevalent in PWR-1E and RWPE-1 cells. We also analyzed CYP1A1 enhancer methylation in human prostate tissue DNA. We do not detect CYP1A1 enhancer methylation in 30 DNA samples isolated from noncancerous prostate tissue. In contrast, 11 of 30 prostate tumor DNA samples have detectable CYP1A1 enhancer methylation, indicating that it is hypermethylated in prostate tumors. This is the first report that shows that CYP1A1 is aberrantly hypermethylated in human prostate cancer and has an altered, inaccessible chromatin structure that suppresses its dioxin responsiveness. (Cancer Res 2006; 66(15): 7420-8) (Cancer Res 2006; 66(15): 7420-8)

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				S. T. Okino, L. C. Quattrochi, D. Pookot, M. Iwahashi, and R. Dahiya A Dioxin-Responsive Enhancer 3' of the Human CYP1A2 Gene Mol. Pharmacol., December 1, 2007; 72(6): 1457 - 1465. [Abstract] [Full Text] [PDF]