Format

Send to

Choose Destination
Cancer Discov. 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.

Author information

1
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
2
Institute of Molecular and Cell Biology, Singapore.
3
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore.
4
State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
5
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
6
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
7
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
8
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
9
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, United Kingdom.
10
Cardiovascular and Metabolic Disorders Programme, Duke-NUS Medical School, Singapore.
11
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
12
Department of Urology, Singapore General Hospital, Singapore.
13
Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore.
14
Department of Pathology, Singapore General Hospital, Singapore.
15
Translational Research, Genome Institute of Singapore, Singapore.
16
Institute of Virology, University of Cologne, Fuerst-Pueckler-Strasse, Cologne, Germany.
17
Institute of Molecular and Cell Biology, Singapore. gmstanp@duke-nus.edu.sg teh.bin.tean@singhealth.com.sg.
18
SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.
19
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore. gmstanp@duke-nus.edu.sg teh.bin.tean@singhealth.com.sg.

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.

PMID:
28893800
DOI:
10.1158/2159-8290.CD-17-0375
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center