SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer

被引：158

作者：

Li, Guoqiang ^{[1
,3
]}

Ci, Weimin ^{[2
]}

Karmakar, Subhradip ^{[4
,5
,6
]}

Chen, Ke ^{[1
]}

Dhar, Ruby ^{[4
,5
,6
]}

Fan, Zhixiang ^{[10
]}

Guo, Zhongqiang ^{[1
,11
]}

Zhang, Jing ^{[1
]}

Ke, Yuwen ^{[1
]}

Wang, Lu ^{[1
,3
]}

Zhuang, Min ^{[13
]}

Hu, Shengdi ^{[14
]}

Li, Xuesong ^{[11
]}

Zhou, Liqun ^{[11
]}

Li, Xianghong ^{[12
]}

Calabrese, Matthew F. ^{[15
]}

Watson, Edmond R. ^{[15
]}

Prasad, Sandip M. ^{[8
]}

Rinker-Schaeffer, Carrie ^{[8
]}

Eggener, Scott E. ^{[8
]}

Stricker, Thomas ^{[4
,5
,9
]}

Tian, Yong ^{[14
]}

Schulman, Brenda A. ^{[15
,16
]}

Liu, Jiang ^{[1
]}

White, Kevin P. ^{[4
,5
,6
,7
]}

机构：

[1] Chinese Acad Sci, Beijing Inst Genom, Key Lab Genome Sci & Informat, Beijing 100101, Peoples R China

[2] Chinese Acad Sci, Beijing Inst Genom, Lab Dis Genom & Individualized Med, Beijing 100101, Peoples R China

[3] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[4] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA

[5] Argonne Natl Lab, Chicago, IL 60637 USA

[6] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[7] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA

[8] Univ Chicago, Dept Surg, Urol Sect, Chicago, IL 60637 USA

[9] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[10] Kunming Med Univ, Kunming 650500, Yunnan, Peoples R China

[11] Peking Univ, Hosp 1, Dept Urol, Beijing 100034, Peoples R China

[12] Peking Univ, Canc Hosp, Dept Pathol, Beijing 100142, Peoples R China

[13] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[14] Chinese Acad Sci, Inst Biophys, Lab Anim Res Ctr, Beijing 100101, Peoples R China

[15] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA

[16] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA

来源：

CANCER CELL | 2014年 / 25卷 / 04期

基金：

美国国家科学基金会;

关键词：

RENAL-CELL CARCINOMA; PTEN TUMOR-SUPPRESSOR; PHOSPHATASE-ACTIVITY; INTERFERON-ALPHA; UBIQUITIN LIGASE; PROTEIN; PHOSPHORYLATION; EXPRESSION; HYPOXIA; IDENTIFICATION;

D O I：

10.1016/j.ccr.2014.02.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the proapoptotic molecule Daxx, and the Hedgehog pathway transcription factor Gli2. Knockdown of SPOP specifically kills ccRCC cells, indicating that it may be a promising therapeutic target. Collectively, our results indicate that SPOP serves as a regulatory hub to promote ccRCC tumorigenesis.

引用

页码：455 / 468

页数：14

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