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.
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Cancer Res. 2014 Nov 15;74(22):6542-53. doi: 10.1158/0008-5472.CAN-14-1030. Epub 2014 Sep 16.
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.
雄激素受体 (AR) 是早期和晚期前列腺癌的关键驱动因素，因此全面了解其调控机制非常重要。在这里，我们报告了鉴定出转录因子 CtBP2（羧基末端结合蛋白）基因中多个 AR 结合位点的方法，该基因的遗传变异与前列腺癌易感性有关。值得注意的是，我们发现与前列腺癌发展相关的人类 CTBP2 基因中的 SNP 与 AR 增强子活性相关。CtBP2 高表达与患者预后不良相关，而 CtBP2 沉默则降低了人前列腺癌小鼠异种移植模型中的肿瘤生长。与作为转录共抑制因子的功能一致，CtBP2 通过与 AR 结合到这些基因的启动子增强子上，抑制了前列腺癌细胞中的肿瘤抑制基因和 AR 共抑制因子，如 NCOR 和 RIP140。全基因组表达分析显示对雄激素介导的基因表达有正向影响，CtBP2 沉默被发现增加了 AR 与限制组蛋白修饰的共抑制因子的相互作用。总的来说，我们的研究结果表明，CtBP2 通过调节 AR 和致癌信号来促进前列腺癌的进展。
