Association of USP10 with G3BP2 Inhibits p53 Signaling and Contributes to Poor Outcome in Prostate Cancer.

Abstract

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.Implications: 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. Mol Cancer Res; 16(5); 846-56. ©2018 AACR.