VHL 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 ( 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 profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL 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-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling 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-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

Insights into Epigenetic Remodeling in VHL-Deficient Clear Cell Renal Cell Carcinoma

“…1). Increased expression of ZNF395 had been previously identified as a potential ccRCC biomarker, and this study demonstrated that knockdown of ZNF395 significantly decreased cell proliferation and viability both in vitro and in vivo in two cell line models of ccRCC, A-498 and 786-O, which highlights the importance of this master regulator and its potential as a therapeutic target (6).…”

Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma

“…The copy numbers of 587 ccRCC tissues and 901 paired normal kidney tissues from the TCGA database (KIRC CNV) were obtained. GSE76207 (14) and GSE102101 (15) were obtained from the GEO database (http://www.ncbi.nlm. nih.gov/geo/), and respectively contained 16 and 10 paired tumor and normal kidney tissues.…”

Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma

“…TF peak calls were downloaded from ChIP-seq analyses performed by 39 . For each T/N/d state, enrichment odds ratios was evaluated by a Fisher’s exact test comparing the number of asQTL peaks overlapping TF peaks (i.e.…”