論文

査読有り
2016年8月

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

ONCOTARGET
  • 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

7
31
開始ページ
49107
終了ページ
49121
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.18632/oncotarget.9470
出版者・発行元
IMPACT JOURNALS LLC

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.

Web of Science ® 被引用回数 : 8

リンク情報
DOI
https://doi.org/10.18632/oncotarget.9470
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000385422000023&DestApp=WOS_CPL

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