Abstract
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 noncoding 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. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivoVHL 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 VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, 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. Cancer Discov; 7(11); 1284-305. ©2017 AACR.See related commentary by Ricketts and Linehan, p. 1221This article is highlighted in the In This Issue feature, p. 1201.
Highlights
Clear cell renal cell carcinoma is the most common subtype of kidney cancer, with 338,000 new cases in 2012 worldwide [1]
The von Hippel–Lindau (VHL) mutations co-occurred with somatic mutations of other chromatin modifiers commonly found in Clear cell renal cell carcinoma (ccRCC), including PBRM1 (7/10), SETD2 (1/10), KDM5A (1/10), KDM5C (1/10), ARID1A (1/10), and KMT2C (1/10)
Through comprehensive profiling of histone modifications in primary normal–tumor pairs and cell lines, we generated a compendium of ccRCC-associated promoters and enhancers
Summary
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, with 338,000 new cases in 2012 worldwide [1]. HIF2α-bound distal enhancers activate the protooncogenes MYC [31] and CCND1 [21] and coincide with ccRCC genetic risk alleles Such studies focused on individual enhancers, and the majority of distal elements in ccRCC remain largely unexplored. Compared with promoters that are largely cell-type invariant, distal enhancers integrate multiple lineage- and context-dependent signals, catering to the specialized needs of diverse cell types and diseases [32, 33]. In cancer, such master regulators are frequently located near “superenhancers” or “stretch-enhancers” marked by long stretches of H3K27ac signals [34, 35]. Our results reveal an epigenetic framework by which the major ccRCC-specific driver mutation, VHL, induces de novo enhancers, contributing to oncogenic transcription
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