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

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms13183

2041-1723

Steffen Grampp, James L. Platt, Victoria Lauer, Rafik Salama, Franziska Kranz, Viviana K. Neumann, Sven Wach, Christine Stöhr, Arndt Hartmann, Kai‐Uwe Eckardt, Peter J. Ratcliffe, David R. Mole, Johannes Schödel,

Cancer, Hypoxia, and Metabolism

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.