Androgen receptor functions as a negative transcriptional regulator of DEPTOR, mTOR inhibitor
Androgen receptor functions as a negative transcriptional regulator of DEPTOR, mTOR inhibitor
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DOI：
10.2131/jts.40.753
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发表时间：
2015-12-01
影响因子：
2
通讯作者：
Inouye, Yoshio
中科院分区：
文献类型：
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作者：
Kanno, Yuichiro;Zhao, Shuai;Inouye, Yoshio
研究发现，雄激素受体（AR）和哺乳动物雷帕霉素靶蛋白（mTOR）信号通路之间的相互干扰在前列腺癌细胞增殖中起着至关重要的作用。为了阐明这一机制，我们专注于DEPTOR，一种天然存在的mTOR抑制剂。用AR激动剂二氢睾酮（DHT）处理人AR阳性前列腺癌细胞系LNCaP，以时间依赖性方式抑制DEPTOR mRNA表达。这种抑制被废除的AR拮抗剂比卡鲁胺治疗。通过siRNA敲低DEPTOR mRNA导致70 kDa核糖体蛋白S6激酶1（S6K）（mTORC 1的底物）磷酸化增加，伴随着细胞周期蛋白D1（细胞增殖的正调节因子）表达升高。此外，ChIP分析表明，AR可以结合到AR负责元件样区域内的第4内含子的DEPTOR基因。乙酰化组蛋白H3（Lys9，Lys14）的量减少的DHT处理在这个区域。总之，这些结果表明AR依赖性前列腺癌细胞增殖需要AR直接控制的DEPTOR转录降低。
It has been noticed that crosstalk between androgen receptor (AR) and mammalian target of rapamycin (mTOR) signaling pathways plays a crucial role in the proliferation of prostate cancer cells. To clarify this mechanism, we focused on DEPTOR, a naturally occurring inhibitor of mTOR. The treatment of a human AR-positive prostate cancer cell line, LNCaP, with the AR-agonist dihydrotestosterone (DHT) repressed DEPTOR mRNA expression in a time-dependent manner. This repression was abrogated by treatment with the AR-antagonist bicalutamide. Knockdown of DEPTOR mRNA by siRNA resulted in the increased phosphorylation of 70 kDa ribosomal protein S6 kinase 1 (S6K), a substrate of mTORC1, accompanied by the elevated expression of cyclin D1, a positive regulator of cell proliferation. Furthermore, the ChIP assay demonstrated that AR could bind to AR-responsible element-like region within the 4th intron of the DEPTOR gene. The amount of acetylated histone H3 (Lys9, Lys14) was reduced by the DHT treatment in this region. Taken together, these results propose that AR-dependent prostate cancer cell proliferation requires decreased DEPTOR transcription directly controlled by AR.