VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel Lindau (VHL) tumor suppressor. Roles for non-coding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Super-enhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator, whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/super-enhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase P300 without overtly affecting pre-existing promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.