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

TitleVHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.
Publication TypeJournal Article
Year of Publication2018
AuthorsZhang J, Wu T, Simon J, Takada M, Saito R, Fan C, De Liu X-, Jonasch E, Xie L, Chen X, Yao X, Teh BTean, 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, J Auman T, Perou CM, W Rathmell K, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q
JournalScience
Volume361
Issue6399
Pagination290-295
Date Published2018 07 20
ISSN1095-9203
KeywordsAnimals, 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
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 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.

DOI10.1126/science.aap8411
Alternate JournalScience
PubMed ID30026228
PubMed Central IDPMC6154478