Journal Article

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

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

2016

Overview

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. Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation of MYC .

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 42/41 / 631/208/176 / 631/208/200 / 631/67/395 / 631/67/589/1588/1351 / 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 / Chromosomes, Human, Pair 8 / DNA, Intergenic - genetics / DNA, Intergenic - metabolism / Enhancer Elements, Genetic / Epigenetics / Gene Expression Regulation, Neoplastic / Genetic diversity / Genetic Predisposition to Disease / Genome-Wide Association Study / Genomes / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Kidney cancer / Kidney Neoplasms - genetics / Kidney Neoplasms - metabolism / Kidney Neoplasms - pathology / multidisciplinary / Mutation / Polymorphism, Single Nucleotide / Prostate cancer / Protein Binding / Proteins / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Von Hippel-Lindau Tumor Suppressor Protein - genetics / Von Hippel-Lindau Tumor Suppressor Protein - metabolism