Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer

Nat Commun. 2016 Oct 24:7:13183. doi: 10.1038/ncomms13183.

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL-HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics*
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • Binding Sites
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromatin Immunoprecipitation
  • Chromosomes, Human, Pair 8
  • DNA, Intergenic / genetics
  • DNA, Intergenic / metabolism
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Signal Transduction
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • ARNT protein, human
  • Chromatin
  • DNA, Intergenic
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MYC protein, human
  • PVT1 long-non-coding RNA, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Long Noncoding
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human