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

Authors: Zhang, Jing; Wu, Tao; Simon, Jeremy; Takada, Mamoru; Saito, Ryoichi; Fan, Cheng; Liu, Xian-De; Jonasch, Eric; Xie, Ling; Chen, Xian; Yao, Xiaosai; Teh, Bin Tean; Tan, Patrick; Zheng, Xingnan; Li, Mingjie; Lawrence, Cortney; Fan, Jie; Geng, Jiang; Liu, Xijuan; Hu, Lianxin; Wang, Jun; Liao, Chengheng; Hong, Kai; Zurlo, Giada; Parker, Joel S; Auman, J Todd; Perou, Charles M; Rathmell, W Kimryn; Kim, William Y; Kirschner, Marc W; Kaelin Jr, William G; Baldwin, Albert S; Zhang, Qing

Published In Science, (2018 Jul 20)

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.

PubMed ID: 30026228 Exiting the NIEHS site

MeSH Terms: Animals; Carcinoma, Renal Cell/drug therapy; Carcinoma, Renal Cell/genetics*; Chromatin Immunoprecipitation; Female; Gene Expression Regulation, Neoplastic; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism*; Humans; Hydroxylation; Kidney Neoplasms/drug therapy; Kidney Neoplasms/genetics*; Mice; Mice, SCID; Molecular Targeted Therapy; Mutation; NF-kappa B/metabolism; Oncogenes*; Substrate Specificity; Transcription Factors/genetics; Transcription Factors/metabolism*; Von Hippel-Lindau Tumor Suppressor Protein/genetics; Von Hippel-Lindau Tumor Suppressor Protein/metabolism*

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