Regulation of Androgen-Responsive Transcription by the Chromatin Remodeling Factor CHD8
Regulation of Androgen-Responsive Transcription by the Chromatin Remodeling Factor CHD8
复制标题
DOI：
10.1210/me.2009-0421
复制
发表时间：
2010-06-01
影响因子：
--
通讯作者：
Bochar, Daniel A.
中科院分区：
文献类型：
--
作者：
Menon, Tushar;Yates, Joel A.;Bochar, Daniel A.
雄激素受体（AR）通过其在正常前列腺发育和前列腺癌的出现和进展期间的转录功能介导雄激素的作用。已知AR在靶启动子处组装共激活因子复合物以促进响应于雄激素的转录激活。在这里，我们确定了ATP依赖的染色质重塑因子chromodomain解旋酶DNA结合蛋白8（CHD 8）作为一种新的雄激素反应性转录的辅助调节因子。我们证明CHD 8直接与AR相关，并且CHD 8和AR在雄激素治疗后同时定位于TMPRSS 2增强子。在LNCaP细胞系中，通过小干扰RNA处理降低CHD 8水平严重减少TMPRSS 2基因的雄激素依赖性激活。我们证明，招聘AR的TMPRSS 2启动子在雄激素治疗需要CHD 8。最后，CHD 8促进LNCaP细胞的雄激素刺激的增殖，强调CHD 8的生理重要性。综上所述，我们提出了CHD 8在AR介导的靶基因转录调控中的功能作用的证据。（分子内分泌学24：1165-1174，2010）
The androgen receptor (AR) mediates the effect of androgens through its transcriptional function during both normal prostate development and in the emergence and progression of prostate cancer. AR is known to assemble coactivator complexes at target promoters to facilitate transcriptional activation in response to androgens. Here we identify the ATP-dependent chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8) as a novel coregulator of androgen-responsive transcription. We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8. Finally, CHD8 facilitates androgen-stimulated proliferation of LNCaP cells, emphasizing the physiological importance of CHD8. Taken together, we present evidence of a functional role for CHD8 in AR-mediated transcriptional regulation of target genes. (Molecular Endocrinology 24: 1165-1174, 2010)