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. 2017 Nov;7(11):1284-1305.
doi: 10.1158/2159-8290.CD-17-0375. Epub 2017 Sep 11.

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Xiaosai Yao  1   2 , Jing Tan  3   4 , Kevin Junliang Lim  5 , Joanna Koh  1 , Wen Fong Ooi  1 , Zhimei Li  3 , Dachuan Huang  3 , Manjie Xing  1   5   6 , Yang Sun Chan  1 , James Zhengzhong Qu  1 , Su Ting Tay  5 , Giovani Wijaya  3 , Yue Ning Lam  1 , Jing Han Hong  5 , Ai Ping Lee-Lim  1 , Peiyong Guan  3 , Michelle Shu Wen Ng  2 , Cassandra Zhengxuan He  1 , Joyce Suling Lin  1 , Tannistha Nandi  1 , Aditi Qamra  1   7 , Chang Xu  5   8 , Swe Swe Myint  3 , James O J Davies  9 , Jian Yuan Goh  1 , Gary Loh  1 , Bryan C Tan  10 , Steven G Rozen  5 , Qiang Yu  1 , Iain Bee Huat Tan  1   11 , Christopher Wai Sam Cheng  12 , Shang Li  5 , Kenneth Tou En Chang  13 , Puay Hoon Tan  14 , David Lawrence Silver  9 , Alexander Lezhava  15 , Gertrud Steger  16 , Jim R Hughes  9 , Bin Tean Teh  17   3   5   8   18 , Patrick Tan  19   5   8   18
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VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Xiaosai Yao et al. Cancer Discov. 2017 Nov.

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.

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