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Functional role and tobacco smoking effects on methylation of CYP1A1 gene in prostate cancer

 Yozo Mitsui  ;  Inik Chang  ;  Taku Kato  ;  Yutaka Hashimoto  ;  Soichiro Yamamura  ;  Shinichiro Fukuhara  ;  Darryn K. Wong  ;  Marisa Shiina  ;  Mitsuho Imai-Sumida  ;  Shahana Majid  ;  Sharanjot Saini  ;  Hiroaki Shiina  ;  Koichi Nakajima  ;  Guoren Deng  ;  Rajvir Dahiya  ;  Yuichiro Tanaka 
 ONCOTARGET , Vol.7(31) : 49107-49121, 2016 
Journal Title
Issue Date
Aged ; Aged, 80 and over ; Apoptosis ; Azacitidine/analogs & derivatives ; Azacitidine/chemistry ; Cell Line, Tumor ; CpG Islands ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1A1/metabolism* ; DNA Methylation* ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; Promoter Regions, Genetic ; Prostatic Hyperplasia/genetics ; Prostatic Hyperplasia/metabolism* ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism* ; Sulfites/chemistry ; Tissue Array Analysis ; Tobacco Smoking/adverse effects* ; Xenobiotics/chemistry
cytochrome P450 1A1 ; methylation ; prostate cancer ; tobacco smoking
Cytochrome P450 (CYP) 1A1 is a phase I enzyme that can activate various compounds into reactive forms and thus, may contribute to carcinogenesis. In this study, we investigated the expression, methylation status, and functional role of CYP1A1 on prostate cancer cells. Increased expression of CYP1A1 was observed in all cancer lines (PC-3, LNCaP, and DU145) compared to BPH-1 (P < 0.05); and was enhanced further by 5-aza-2'-deoxycytidine treatment (P < 0.01). Methylation-specific PCR (MSP) and sequencing of bisulfite-modified DNA of the xenobiotic response element (XRE) enhancer site XRE-1383 indicated promoter methylation as a regulator of CYP1A1 expression. In tissue, microarrays showed higher immunostaining of CYP1A1 in prostate cancer than normal and benign prostatic hyperplasia (BPH; P < 0.001), and methylation analyses in clinical specimens revealed significantly lower methylation levels in cancer compared to BPH at all enhancer sites analyzed (XRE-1383, XRE-983, XRE-895; P < 0.01). Interestingly, smoking affected the XRE-1383 site where the methylation level was much lower in cancer tissues from smokers than non-smokers (P < 0.05). CYP1A1 levels are thus increased in prostate cancer and to determine the functional effect of CYP1A1 on cells, we depleted the gene in LNCaP and DU145 by siRNA. We observe that CYP1A1 knockdown decreased cell proliferation (P < 0.05) and increased apoptosis (P < 0.01) in both cell lines. We analyzed genes affected by CYP1A1 silencing and found that apoptosis-related BCL2 was significantly down-regulated. This study supports an oncogenic role for CYP1A1 in prostate cancer via promoter hypomethylation that is influenced by tobacco smoking, indicating CYP1A1 to be a promising target for prostate cancer treatment.
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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
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