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
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Research Support, Non-U.S. Gov't
MeSH terms
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Aryl Hydrocarbon Receptor Nuclear Translocator / genetics*
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Binding Sites
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Carcinoma, Renal Cell / genetics*
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Chromatin / chemistry
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Chromatin / metabolism
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Chromatin Immunoprecipitation
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Chromosomes, Human, Pair 8
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DNA, Intergenic / genetics
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DNA, Intergenic / metabolism
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Enhancer Elements, Genetic
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Gene Expression Regulation, Neoplastic*
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Genetic Predisposition to Disease
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Genome-Wide Association Study
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Kidney Neoplasms / genetics*
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Polymorphism, Single Nucleotide*
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Protein Binding
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism
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Signal Transduction
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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ARNT protein, human
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Chromatin
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DNA, Intergenic
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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MYC protein, human
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PVT1 long-non-coding RNA, human
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Proto-Oncogene Proteins c-myc
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RNA, Long Noncoding
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Aryl Hydrocarbon Receptor Nuclear Translocator
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human