The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity.
The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity.
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DOI：
10.1016/j.ccr.2013.02.016
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发表时间：
2013-03-18
期刊：
影响因子：
50.3
通讯作者：
Ronai ZA
中科院分区：
文献类型：
--
作者：
Qi J;Tripathi M;Mishra R;Sahgal N;Fazli L;Ettinger S;Placzek WJ;Claps G;Chung LW;Bowtell D;Gleave M;Bhowmick N;Ronai ZA
雄激素受体（AR）在去势抵抗性前列腺癌（CRPC）的发展中起着核心作用，了解其调控机制有望克服治疗CRPC的挑战。我们证明了泛素连接酶Siah2靶向一个选择的ncor1结合的、转录不活跃的AR进行泛素依赖性降解，从而促进与脂质代谢、细胞运动和增殖有关的AR靶基因的表达。体外和体内雄激素剥夺条件下前列腺癌细胞的生长都需要Siah2，抑制Siah2可促进去势后前列腺癌的消退。值得注意的是，Siah2在人CRPCs中的表达明显增加。总之，我们发现泛素连接酶Siah2对AR转录活性的选择性调控对CRPC的发育很重要。
Understanding the mechanism underlying the regulation of the androgen receptor (AR), a central player in the development of castration-resistant prostate cancer (CRPC), holds promise for overcoming the challenge of treating CRPC. We demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally-inactive AR for ubiquitin-dependent degradation, thereby promoting expression of select AR target genes implicated in lipid metabolism, cell motility, and proliferation. Siah2 is required for prostate cancer cell growth under androgen-deprivation conditions in vitro and in vivo, and Siah2 inhibition promotes prostate cancer regression upon castration. Notably, Siah2 expression is markedly increased in human CRPCs. Collectively, we find that selective regulation of AR transcriptional activity by the ubiquitin ligase Siah2 is important for CRPC development.
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