Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer.
Author(s): Grampp S, Platt J, Lauer V, Salama R, Kranz F, Neumann V, Wach S, Stoehr C, Hartmann A, Eckardt K, Ratcliffe P, Mole D, Schoedel J
Publication year: 2016
Pages range: 13183
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.
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APA: Grampp, S., Platt, J., Lauer, V., Salama, R., Kranz, F., Neumann, V.,... Schoedel, J. (2016). Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer. Nature Communications, 7, 13183. https://dx.doi.org/10.1038/ncomms13183
MLA: Grampp, Steffen, et al. "Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer." Nature Communications 7 (2016): 13183.