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

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

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)290-295
Number of pages6
JournalScience
Volume361
Issue number6399
DOIs
StatePublished - Jul 20 2018

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ASJC Scopus subject areas

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Cite this

Zhang, J., Wu, T., Simon, J., Takada, M., Saito, R., Fan, C., Liu, X. D., Jonasch, E., Xie, L., Chen, X., Yao, X., Teh, B. T., Tan, P., Zheng, X., Li, M., Lawrence, C., Fan, J., Geng, J., Liu, X., ... Zhang, Q. (2018). VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science, 361(6399), 290-295. https://doi.org/10.1126/science.aap8411