<i>VHL</i> Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Abstract

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau (<i>VHL</i>) tumor suppressor. Roles for noncoding <i>cis</i>-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. Superenhancer profiling identified <i>ZNF395</i> as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination <i>in vitro</i> and <i>in vivo</i><i>VHL</i> loss predominantly drives enhancer/superenhancer 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 preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as <i>VHL</i> may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.<b>Significance:</b> Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered <i>cis</i>-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of <i>VHL</i>, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. <i>Cancer Discov; 7(11); 1284-305. ©2017 AACR.</i><i>See related commentary by Ricketts and Linehan, p. 1221</i><i>This article is highlighted in the In This Issue feature, p. 1201</i>.