Zhang Zheng, Jin Bo, Jin Yaqiong, Huang Shengquan, Niu Xiaohua, Mao Zebin, Xin Dianqi
Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034, China.
Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034, China.
Exp Cell Res. 2017 Jan 1;350(1):1-8. doi: 10.1016/j.yexcr.2016.10.013. Epub 2016 Oct 15.
Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the -851 to -836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis.
雄激素（AR）在前列腺癌的发生和发展中起着重要作用。研究表明，AR主要通过雄激素激活的AR发挥作用，该AR与靶基因调控区域中的雄激素反应元件（AREs）结合，以调节雄激素反应性基因的转录，因此，鉴定AR下游靶基因对于理解雄激素在前列腺癌中的功能至关重要。在本研究中，我们的结果表明，用雄激素处理LNCaP细胞可诱导PTTG1表达，而该表达被雄激素受体拮抗剂比卡鲁胺阻断。使用PTTG1启动子缺失突变体的生物信息学分析和实验表明，PTTG1启动子包含一个推定的雄激素反应元件（ARE），其位于启动子的-851至-836区域。通过染色质免疫沉淀（ChIP）分析证实了雄激素激活的雄激素受体（AR）与该ARE结合。此外，使用短发夹RNA敲低PTTG1表达可显著降低雄激素诱导的LNCaP细胞生长和侵袭。此外，我们发现PTTG1在转移性前列腺癌组织中高表达。这些结果表明，PTTG1是雄激素受体的一个新的下游靶基因，并参与前列腺癌的增殖和转移。
