VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Cancer Discov. 2017 Nov;7(11):1284-1305. doi: 10.1158/2159-8290.CD-17-0375. Epub 2017 Sep 11.


Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivoVHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305. ©2017 AACR.See related commentary by Ricketts and Linehan, p. 1221This article is highlighted in the In This Issue feature, p. 1201.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Carcinogenesis / genetics
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Chromatin
  • DNA-Binding Proteins / genetics*
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mutation
  • Oncogenes / genetics
  • Promoter Regions, Genetic / genetics
  • Regulatory Sequences, Nucleic Acid / genetics
  • Transcription Factors / genetics*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • p300-CBP Transcription Factors / genetics*


  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • DNA-Binding Proteins
  • Transcription Factors
  • ZNF395 protein, human
  • endothelial PAS domain-containing protein 1
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human