TY - JOUR
T1 - Association of USP10 with G3BP2 inhibits p53 signaling and contributes to poor outcome in prostate cancer
AU - Takayama, Ken ichi
AU - Suzuki, Takashi
AU - Fujimura, Tetsuya
AU - Takahashi, Satoru
AU - Inoue, Satoshi
N1 - Funding Information:
This work was supported by grants of the Cell innovation Program, the P-DIRECT and the P-CREATE from Ministry of Education, Culture, Sports, Science and Technology, Japan (S. Inoue), by the MEXT, Japan, by grants (K. Takayama and S. Inoue) from the JSPS (number 15K15581, 15K15353, 17H04334), Japan, by the Program for Promotion of Fundamental Studies in Health Sciences (S. Inoue), NIBIO, Japan, grants from Takeda Science Foundation, Japan (K. Takayama and S. Inoue), grants from the Terumo foundation for life sciences and arts, Japan (K. Takayama), and grants from the NOVARTIS Foundation for the Promotion of Science, Japan (K. Takayama).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044600595&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044600595&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0471
DO - 10.1158/1541-7786.MCR-17-0471
M3 - Article
C2 - 29378906
AN - SCOPUS:85044600595
VL - 16
SP - 846
EP - 856
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 5
ER -
