title: Cytochrome P450 1B1 is overexpressed and regulated by hypomethylation in prostate cancer.
abstract: OBJECTIVE
  Cytochrome P450 1B1 (CYP1B1), a dioxin inducible member of the CYP supergene family, is overexpressed in various human malignancies including prostate cancer. We hypothesized that promoter/enhancer CpG methylation contributes to the regulation of CYP1B1 expression in human prostate tissue.
  
  
  METHODS
  Expression and induction of the CYP1B1 gene in clinical prostate tissues and prostate cancer cell lines were investigated. The methylation status of the CYP1B1 gene was analyzed in 175 prostate cancer and 96 benign prostatic hyperplasia samples using methylation-specific PCR (MSP) and bisulfite-modified DNA sequencing. MSP primers covered dioxin response elements (DRE) and Sp1 sites that are important for the expression of CYP1B1.
  
  
  RESULTS
  Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. In prostate cancer cells, CYP1B1 mRNA was induced by 2,3,7,8-tetrachlorodigenzo-p-dioxin (TCDD) and/or demethylation agent (5-aza-2-deoxycytidine). There was no change in the expressions of AhR and ARNT. Methylation of promoter/enhancer regions was significantly higher in benign prostatic hyperplasia compared with prostate cancer. MSP-positive patients had significantly lower risk for prostate cancer as compared with MSP-negative patients. There was no correlation between CYP1B1 methylation status and clinicopathologic features.
  
  
  CONCLUSIONS
  CYP1B1 is overexpressed in prostate cancer and regulated by hypomethylation of its promoter/enhancer region. This is the first report about CYP1B1 regulation in human clinical prostate samples showing that hypomethylation of the CYP1B1 gene may play an important role in prostate cancer.
authors.affiliation: Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokizane
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.forename: Mikio
authors.initials: M
authors.lastname: Igawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Shinji
authors.initials: S
authors.lastname: Urakami
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kawakami
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ogishima
authors.forename: Steven T
authors.initials: ST
authors.lastname: Okino
authors.forename: Long-Cheng
authors.initials: LC
authors.lastname: Li
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuyama
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D065633:Cytochrome P-450 CYP1B1; D019175:DNA Methylation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D001374:Azacitidine