| Literature DB >> 30026228 |
Jing Zhang1,2, Tao Wu3, Jeremy Simon1,4, Mamoru Takada1, Ryoichi Saito1, Cheng Fan1, Xian-De Liu5, Eric Jonasch5, Ling Xie6, Xian Chen6, Xiaosai Yao7,8, Bin Tean Teh8,9,10, Patrick Tan7,10, Xingnan Zheng1, Mingjie Li1, Cortney Lawrence1, Jie Fan11, Jiang Geng12, Xijuan Liu1, Lianxin Hu1, Jun Wang1, Chengheng Liao1, Kai Hong1, Giada Zurlo1, Joel S Parker1, J Todd Auman1, Charles M Perou1, W Kimryn Rathmell13, William Y Kim1, Marc W Kirschner3, William G Kaelin14, Albert S Baldwin1, Qing Zhang15,2,16.
Abstract
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 κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.Entities:
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Year: 2018 PMID： 30026228 PMCID： PMC6154478 DOI： 10.1126/science.aap8411
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728