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

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2016MP66-04 CIGARETTE SMOKING AND CYP1A1 ENHANCE PROSTATE CANCER PROGRESSION THROUGH DNA PROMOTER HYPOMETHYLATION Yozo Mitsui, Inik Chang, Shinichiro Fukuhara, Miho Hiraki, Naoko Arichi, Hiroaki Yasumoto, Hiroaki Shiina, Rajvir Dahiya, and Yuichiro Tanaka Yozo MitsuiYozo Mitsui More articles by this author , Inik ChangInik Chang More articles by this author , Shinichiro FukuharaShinichiro Fukuhara More articles by this author , Miho HirakiMiho Hiraki More articles by this author , Naoko ArichiNaoko Arichi More articles by this author , Hiroaki YasumotoHiroaki Yasumoto More articles by this author , Hiroaki ShiinaHiroaki Shiina More articles by this author , Rajvir DahiyaRajvir Dahiya More articles by this author , and Yuichiro TanakaYuichiro Tanaka More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1278AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail 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<0.01). Importantly, smoking affected the methylation status of the XRE5 site, where the methylation level was significantly lower in smoking PC tissues than in non-smoking PC tissues (P<0.05). In vitro, using a CYP1A1 siRNA, we found that CYP1A1 knockdown significantly decreased cell proliferation and increased apoptosis in both cell lines. We analyzed genes affected by CYP1A1 knockdown and observed that the apoptosis-related BCL2 gene was significantly down-regulated. In addition, CYP1A1 knockdown reduced AKT phosphorylation in both cell lines. This suggests that CYP1A1 may act as an upstream activator of the PI3K-AKT signaling pathway and enhance the transcriptional activation of BCL2. CONCLUSIONS CYP1A1 is an important oncogene in PC that is up-regulated by DNA promoter demethylation. Conversion from high to low methylation at the CYP1A1 enhancer caused by tobacco smoking is probably associated with carcinogen activation through increased CYP1A1 expression. Furthermore, CYP1A1 may have its own oncogenic function and promote PC proliferation and survival via dysregulation of BCL2. Altogether our findings emphasize that tobacco smoking may contribute to the pathogenesis of PC and indicates that inhibition of CYP1A1 may have therapeutic potential. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e874 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Yozo Mitsui More articles by this author Inik Chang More articles by this author Shinichiro Fukuhara More articles by this author Miho Hiraki More articles by this author Naoko Arichi More articles by this author Hiroaki Yasumoto More articles by this author Hiroaki Shiina More articles by this author Rajvir Dahiya More articles by this author Yuichiro Tanaka More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...