Menon Tushar, Yates Joel A, Bochar Daniel A
The Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0606, USA.
Mol Endocrinol. 2010 Jun;24(6):1165-74. doi: 10.1210/me.2009-0421. Epub 2010 Mar 22.
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.
雄激素受体（AR）在正常前列腺发育以及前列腺癌的发生和发展过程中，通过其转录功能介导雄激素的作用。已知AR会在靶启动子处组装共激活因子复合物，以促进对雄激素的转录激活。在此，我们鉴定出ATP依赖的染色质重塑因子染色质结构域解旋酶DNA结合蛋白8（CHD8）是雄激素应答转录的一种新型共调节因子。我们证明CHD8直接与AR相互作用，并且在雄激素处理后，CHD8和AR同时定位于TMPRSS2增强子。在LNCaP细胞系中，通过小干扰RNA处理降低CHD8水平会严重减弱雄激素依赖的TMPRSS2基因激活。我们证明，雄激素处理后AR募集到TMPRSS2启动子需要CHD8。最后，CHD8促进LNCaP细胞的雄激素刺激增殖，强调了CHD8的生理重要性。综上所述，我们提供了CHD8在AR介导的靶基因转录调控中发挥功能作用的证据。
