title: CtBP2 modulates the androgen receptor to promote prostate cancer progression.
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.
authors.affiliation: 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.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: 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.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.affiliation: Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000368:Aged; D000429:Alcohol Oxidoreductases / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000502:physiology; D018450:Disease Progression; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000209:etiology / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: C410798:AR protein, human; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D011944:Receptors, Androgen; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; C096794:C-terminal binding protein