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      CtBP2 modulates the androgen receptor to promote prostate cancer progression.

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          Abstract

          The androgen receptor (AR) is the key driver of both early and advanced prostate cancer, making a complete understanding of its regulation important. Here, we report the identification of multiple AR-binding sites in the gene encoding the transcription factor CtBP2 (carboxyl terminal-binding protein), genetic variations of which have been associated with prostate cancer susceptibility. Notably, we found that SNPs in the human CTBP2 gene that were associated with prostate cancer development were correlated with AR-enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human prostate cancer. Consistent with its function as a transcriptional corepressor, CtBP2 repressed tumor-suppressor genes and AR corepressors in prostate cancer cells, such as NCOR and RIP140, by binding with AR to the promoter enhancers of these genes. Global gene-expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with corepressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling.

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          Author and article information

          Journal
          Cancer Res.
          Cancer research
          1538-7445
          0008-5472
          Nov 15 2014
          : 74
          : 22
          Affiliations
          [1 ] Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Department of Geriatric Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
          [2 ] Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
          [3 ] Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
          [4 ] Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
          [5 ] Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Department of Geriatric Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan. INOUE-GER@h.u-tokyo.ac.jp.
          Article
          0008-5472.CAN-14-1030
          10.1158/0008-5472.CAN-14-1030
          25228652
          6d47ce37-eb37-4b13-b258-c8c5549130d4
          ©2014 American Association for Cancer Research.
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