VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

被引：151

作者：

Zhang, Jing ^{[1
,2
]}

Wu, Tao ^{[3
]}

Simon, Jeremy ^{[1
,4
]}

Takada, Mamoru ^{[1
]}

Saito, Ryoichi ^{[1
]}

Fan, Cheng ^{[1
]}

Liu, Xian-De ^{[5
]}

Jonasch, Eric ^{[5
]}

Xie, Ling ^{[6
]}

Chen, Xian ^{[6
]}

Yao, Xiaosai ^{[7
,8
]}

Teh, Bin Tean ^{[8
,9
,10
]}

Tan, Patrick ^{[7
,10
]}

Zheng, Xingnan ^{[1
]}

Li, Mingjie ^{[1
]}

Lawrence, Cortney ^{[1
]}

Fan, Jie ^{[11
]}

Geng, Jiang ^{[12
]}

Liu, Xijuan ^{[1
]}

Hu, Lianxin ^{[1
]}

Wang, Jun ^{[1
]}

Liao, Chengheng ^{[1
]}

Hong, Kai ^{[1
]}

Zurlo, Giada ^{[1
]}

Parker, Joel S. ^{[1
]}

Auman, J. Todd ^{[1
]}

Perou, Charles M. ^{[1
]}

Rathmell, W. Kimryn ^{[13
]}

Kim, William Y. ^{[1
]}

Kirschner, Marc W. ^{[2
]}

Kaelin, William G., Jr. ^{[14
]}

Baldwin, Albert S. ^{[1
]}

Zhang, Qing ^{[1
,2
,15
]}

机构：

[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[3] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[4] Univ N Carolina, Dept Genet, Neurosci Ctr, Chapel Hill, NC 27599 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[6] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

[7] Genome Inst Singapore, Canc Therapeut & Stratified Oncol, Singapore 138672, Singapore

[8] Inst Mol & Cell Biol, Singapore 138673, Singapore

[9] Natl Canc Ctr, Dept Med Sci, Lab Canc Epigenome, Singapore 169610, Singapore

[10] Duke NUS Med Sch, Canc & Stem Cell Biol Program, Singapore 169857, Singapore

[11] Fudan Univ, Huashan Hosp, Dept Pathol, Shanghai, Peoples R China

[12] Tongji Univ, Shanghai Peoples Hosp 10, Dept Urol, Shanghai, Peoples R China

[13] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol & Oncol,Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA

[14] Harvard Med Sch, Howard Hughes Med Inst, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[15] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

来源：

SCIENCE | 2018年 / 361卷 / 6399期

基金：

英国医学研究理事会;

关键词：

HIF-ALPHA; PROLYL HYDROXYLATION; COMPLEX; EXPRESSION; MUTATIONS; CYTOTOXICITY; ANTAGONIST; CANCER;

D O I：

10.1126/science.aap8411

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor kappa B activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

引用

页码：290 / 295

页数：6

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