MP66-04 CIGARETTE SMOKING AND CYP1A1 ENHANCE PROSTATE CANCER PROGRESSION THROUGH DNA PROMOTER HYPOMETHYLATION

INTRODUCTION AND OBJECTIVES: Several epidemiologic reports using large cohorts suggest that tobacco smoking may be associated with prostate cancer (PC). Cytochrome P450 1A1 (CYP1A1) may play an important role in the initiation of various cancers including PC. However, the mechanisms of overexpression of CYP1A1 and smoking in PC have never been investigated. We assessed whether impaired regulation of CYP1A1 through DNA hypomethylation could be involved in smoking and contribute to the pathogenesis of PC. METHODS: We studied 3 PC cell lines, 69 benign hyperplasia (BPH) and 176 PC samples, using methylation-specific PCR analysis to focus on 3 regions of the CYP1A1 enhancer carrying a xenobiotic responsive element (XRE). In addition, we depleted the gene in LNCaP and DU145 by siRNA to validate its biological role in tumorigenesis. RESULTS: In all PC cell lines, CYP1A1 expression was enhanced after 5-aza-2-deoxycitidine treatment and bisulfite DNA sequencing confirmed hypermethylation at the CYP1A1 enhancer, indicating DNA promoter CpG methylation as a regulator of CYP1A1 expression. The level of methylation of CYP1A1 enhancer was significantly lower in PC as compared to BPH samples at all three enhancer sites (P