Liu Chunhua, Liao Zhaoping, Duan Xiuzhi, Yu Pan, Kong Piaoping, Tao Zhihua, Liu Weiwei
Department of Blood Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Front Oncol. 2021 Apr 1;11:641496. doi: 10.3389/fonc.2021.641496. eCollection 2021.
In the progression of castration-resistant prostate cancer (CRPC), the androgen receptor (AR) that serves as a transcription factor becomes the most remarkable molecule. The transcriptional activity of AR is regulated by various coregulators. As a result, altered expression levels, an aberrant location or activities of coregulators promote the development of prostate cancer. We describe herein results showing that compared with androgen-dependent prostate cancer (ADPC) cells, AR nuclear translocation capability is enhanced in androgen-independent prostate cancer (AIPC) cells. To gain insight into whether AR coregulators are responsible for AR translocation capability, we performed coimmunoprecipitation (CO-IP) coupled with LC-MS/MS to screen 27 previously reported AR cofactors and 46 candidate AR cofactors. Furthermore, one candidate, myosin heavy chain 9 (MYH9), was identified and verified as a novel AR cofactor. Interestingly, the distribution of MYH9 was in both the cytoplasmic and nuclear compartments yet was enriched in the nucleus when AR was knocked down by AR shRNA, suggesting that the nuclear translocation of MYH9 was negatively regulated by AR. In addition, we found that blebbistatin, an inhibitor of MYH9, not only promoted AR nuclear translocation but also enhanced the expression of the AR target gene PSA, which indicates that MYH9 represses nuclear AR signaling. Taken together, our findings reveal that MYH9 appears to be a novel corepressor of AR plays a pivotal role in the progression of CRPC.
在去势抵抗性前列腺癌（CRPC）的进展过程中，作为转录因子的雄激素受体（AR）成为最显著的分子。AR的转录活性受多种共调节因子调控。因此，共调节因子表达水平的改变、异常定位或活性促进了前列腺癌的发展。我们在此描述的结果表明，与雄激素依赖性前列腺癌（ADPC）细胞相比，雄激素非依赖性前列腺癌（AIPC）细胞中AR的核转位能力增强。为了深入了解AR共调节因子是否负责AR的转位能力，我们进行了免疫共沉淀（CO-IP）结合液相色谱-串联质谱（LC-MS/MS），以筛选27种先前报道的AR辅因子和46种候选AR辅因子。此外，鉴定并验证了一种候选蛋白，肌球蛋白重链9（MYH9），作为一种新型的AR辅因子。有趣的是，MYH9的分布在细胞质和细胞核中均有，但当用AR短发夹RNA（shRNA）敲低AR时，其在细胞核中富集，这表明MYH9的核转位受AR负调控。此外，我们发现MYH9的抑制剂blebbistatin不仅促进AR核转位，还增强了AR靶基因前列腺特异性抗原（PSA）的表达，这表明MYH9抑制核AR信号传导。综上所述，我们的研究结果表明，MYH9似乎是一种新型的AR共抑制因子，在CRPC的进展中起关键作用。
