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

Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu X, Hu L, Wang J, Liao C, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q
Science. 2018 361 (6399): 290-295

PMID: 30026228 · PMCID: PMC6154478 · DOI:10.1126/science.aap8411

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 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.

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (18)

Animals Carcinoma, Renal Cell Chromatin Immunoprecipitation Female Gene Expression Regulation, Neoplastic Homeodomain Proteins Humans Hydroxylation Kidney Neoplasms Mice Mice, SCID Molecular Targeted Therapy Mutation NF-kappa B Oncogenes Substrate Specificity Transcription Factors Von Hippel-Lindau Tumor Suppressor Protein

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