Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Mol Cancer Res. 2018 May;16(5):846-856. doi: 10.1158/1541-7786.MCR-17-0471. Epub 2018 Jan 29.
Ubiquitin-specific protease 10 (USP10) is known to deubiquitylate its target proteins, mainly to enhance their stabilities. USP10 maintains p53 protein levels and controls epigenetic changes induced by the androgen receptor (AR). GTPase-activating protein-binding protein 2 (G3BP2), an androgen-responsive gene, is known as the main component of stress granules (SG) that interacts with USP10 in SGs. This study explores the roles of USP10 in prostate cancer progression in p53, G3BP2, and AR signaling. Using chromatin immunoprecipitation (ChIP) and sequence analysis, it was found that USP10 is transcriptionally induced with AR recruitment to an intronic region. Furthermore, USP10 regulates androgen-mediated signaling and cell growth. USP10 maintained G3BP2 protein stability by reducing polyubiquitylation. G3BP2-dependent growth activation and p53 nuclear export that reduced p53 signaling were repressed by USP10 knockdown. Clinically, USP10 was expressed primarily in the cytoplasm of prostate cancer tissues. High levels of USP10 expression were strongly correlated with high levels of AR, G3BP2, and p53 in the cytoplasm. High expression of USP10 was significantly associated with poor prognosis of patients with prostate cancer. Taken together, USP10 has a repressive effect on p53 signaling for cell growth by regulating G3BP2 expression. These findings highlight an important oncogenic aspect of USP10 through its modulation of the p53-G3BP2 complex and AR signaling in prostate cancer. These findings elucidate the oncogenic role of USP10 in prostate cancer through an increase in G3BP2 protein that inhibits p53 activity, in addition to the promotion of AR signaling. .
泛素特异性蛋白酶 10（USP10）已知可去泛素化其靶蛋白，主要是增强它们的稳定性。USP10 维持 p53 蛋白水平，并控制雄激素受体（AR）诱导的表观遗传变化。GTPase 激活蛋白结合蛋白 2（G3BP2）是一种雄激素反应基因，是应激颗粒（SG）的主要成分，它与 SG 中的 USP10 相互作用。本研究探讨了 USP10 在 p53、G3BP2 和 AR 信号转导中的作用，在前列腺癌的进展。通过染色质免疫沉淀（ChIP）和序列分析，发现 USP10 是通过 AR 募集到内含子区域而被转录诱导的。此外，USP10 调节雄激素介导的信号转导和细胞生长。USP10 通过减少多泛素化来维持 G3BP2 蛋白稳定性。USP10 敲低抑制了 G3BP2 依赖性生长激活和减少 p53 信号转导的 p53 核输出。临床上，USP10 主要在前列腺癌组织的细胞质中表达。USP10 高水平表达与细胞质中 AR、G3BP2 和 p53 的高水平密切相关。USP10 高表达与前列腺癌患者预后不良显著相关。总之，USP10 通过调节 G3BP2 的表达对细胞生长的 p53 信号转导具有抑制作用。这些发现强调了 USP10 通过其在前列腺癌中的 p53-G3BP2 复合物和 AR 信号转导的调节，具有重要的致癌作用。这些发现通过增加抑制 p53 活性的 G3BP2 蛋白，以及促进 AR 信号转导，阐明了 USP10 在前列腺癌中的致癌作用。
