Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Oncogene. 2018 Feb 1;37(5):638-650. doi: 10.1038/onc.2017.371. Epub 2017 Oct 9.
Androgen receptor (AR) activation is critical for prostate cancer (PCa) development and progression, including castration resistance. The nuclear export signal of AR (NES) has an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NES. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin-ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in PCa specimens and its expression was correlated with Gleason scores and prostate-specific antigen recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to PCa progression through Siah2.
雄激素受体（AR）的激活对前列腺癌（PCa）的发展和进展至关重要，包括去势抵抗。AR 的核输出信号（NES）在 AR 细胞内运输和蛋白酶体依赖性降解中起重要作用。在这里，我们使用酵母诱变筛选鉴定了 RNA 解旋酶 DHX15 作为一种新型 AR 共激活因子，并揭示 DHX15 通过调节 Siah2 介导的 AR 泛素化来调节 AR 活性，而不依赖其 ATP 酶活性。DHX15 和 Siah2 通过 NES 与 AR 形成复合物。DHX15 稳定 Siah2 并增强其 E3 泛素连接酶活性，从而激活 AR。重要的是，DHX15 在 PCa 标本中上调，其表达与 Gleason 评分和前列腺特异性抗原复发相关。此外，DHX15 免疫染色与 Siah2 相关。最后，DHX15 敲低抑制了小鼠 C4-2 前列腺肿瘤异种移植物的生长。总之，我们的数据表明，DHX15 通过 Siah2 增强 AR 的转录活性并促进 PCa 的进展。
