Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer

被引：66

作者：

Ashikari, D. ^{[1
,2
]}

Takayama, K. ^{[1
,3
]}

Tanaka, T. ^{[4
,5
]}

Suzuki, Y. ^{[6
]}

Obinata, D. ^{[1
,2
,3
]}

Fujimura, T. ^{[7
]}

Urano, T. ^{[1
]}

Takahashi, S. ^{[2
]}

Inoue, S. ^{[1
,3
,8
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Dept Antiaging Med, Tokyo, Japan

[2] Nihon Univ, Sch Med, Dept Urol, Tokyo, Japan

[3] Tokyo Metropolitan Inst Gerontol, Dept Funct Biogerontol, Tokyo, Japan

[4] Chiba Univ, Grad Sch Med, Dept Clin Cell Biol, Chiba, Japan

[5] Chiba Univ, Grad Sch Med, Div Endocrinol & Metab, Chiba, Japan

[6] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Lab Funct Genom, Chiba, Japan

[7] Univ Tokyo, Grad Sch Med, Dept Urol, Tokyo, Japan

[8] Saitama Med Univ, Res Ctr Genom Med, Div Gene Regulat & Signal Transduct, Hidaka, Japan

来源：

ONCOGENE | 2017年 / 36卷 / 45期

关键词：

GTPASE-ACTIVATING PROTEIN; BINDING-PROTEINS; RECEPTOR; MDM2; PROMOTES; CELLS; EXPRESSION; NETWORK; RNA; TUMORIGENESIS;

D O I：

10.1038/onc.2017.225

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The androgen receptor (AR) has a central role in prostate cancer progression, particularly treatment-resistance disease including castration-resistant prostate cancer. Loss of the p53 tumor suppressor, a nuclear transcription factor, is also known to contribute to prostate malignancy. Here we report that p53 is translocated to the cytoplasm by androgen-mediated induction of G3BP2, a newly described direct target gene of AR. G3BP2 induces both cell cycle progression and blocks apoptosis. Translocation of p53 is regulated by androgen-dependent sumoylation mediated by the G3BP2-interacting SUMO-E3 ligase, RanBP2. G3BP2 knockdown results in reduced tumor growth and increased nuclear p53 accumulation in mouse xenograft models of prostate cancer with or without long-term androgen deprivation. Moreover, strong cytoplasmic p53 localization is correlated clinically with elevated G3BP2 expression and predicts poor prognosis and disease progression to the hormone-refractory state. Our findings reveal a new AR-mediated mechanism of p53 inhibition that promotes treatment-resistant prostate cancer.

引用

页码：6272 / 6281

页数：10

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