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

Science. 2018 Jul 20;361(6399):290-295. doi: 10.1126/science.aap8411.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*

Substances

  • Homeodomain Proteins
  • NF-kappa B
  • Transcription Factors
  • ZHX2 protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human