Cytochrome P450 1B1 is overexpressed and regulated by hypomethylation in prostate cancer.
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.
Tokizane
Takashi
T
Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA.
Shiina
Hiroaki
H
Igawa
Mikio
M
Enokida
Hideki
H
Urakami
Shinji
S
Kawakami
Toshifumi
T
Ogishima
Tatsuya
T
Okino
Steven T
ST
Li
Long-Cheng
LC
Tanaka
Yuichiro
Y
Nonomura
Norio
N
Okuyama
Akihiko
A
Dahiya
Rajvir
R
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
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D001374:Azacitidine