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Title: VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma
Authors: Yao, X
Tan, J
Lim, K.J 
Koh, J
Ooi, W.F
Li, Z
Huang, D
Xing, M
Chan, Y.S
Qu, J.Z
Tay, S.T 
Wijaya, G
Lam, Y.N
Hong, J.H 
Lee-Lim, A.P
Guan, P
Ng, M.S.W
He, C.Z
Lin, J.S
Nandi, T
Qamra, A 
Xu, C 
Myint, S.S
Davies, J.O.J
Goh, J.Y
Loh, G
Tan, B.C
Rozen, S.G 
Yu, Q 
Tan, I.B.H 
Cheng, C.W.S 
Li, S 
Chang, K.T.E 
Tan, P.H
Silver, D.L 
Lezhava, A
Steger, G
Hughes, J.R
Teh, B.T 
Tan, P 
Keywords: chemokine receptor CXCR4
glucose transporter 1
hypoxia inducible factor 1alpha
vasculotropin A
von Hippel Lindau protein
basic helix loop helix transcription factor
DNA binding protein
endothelial PAS domain-containing protein 1
histone acetyltransferase PCAF
p300-CBP-associated factor
transcription factor
VHL protein, human
von Hippel Lindau protein
ZNF395 protein, human
controlled study
DNA methylation
gene activation
gene expression
gene sequence
human cell
polymerase chain reaction
principal component analysis
promoter region
protein deficiency
protein interaction
renal cell carcinoma
enhancer region
gene expression regulation
regulatory sequence
renal cell carcinoma
tumor cell line
Basic Helix-Loop-Helix Transcription Factors
Carcinoma, Renal Cell
Cell Line, Tumor
DNA-Binding Proteins
Enhancer Elements, Genetic
Gene Expression Regulation, Neoplastic
p300-CBP Transcription Factors
Promoter Regions, Genetic
Regulatory Sequences, Nucleic Acid
Transcription Factors
Von Hippel-Lindau Tumor Suppressor Protein
Issue Date: 2017
Citation: Yao, X, Tan, J, Lim, K.J, Koh, J, Ooi, W.F, Li, Z, Huang, D, Xing, M, Chan, Y.S, Qu, J.Z, Tay, S.T, Wijaya, G, Lam, Y.N, Hong, J.H, Lee-Lim, A.P, Guan, P, Ng, M.S.W, He, C.Z, Lin, J.S, Nandi, T, Qamra, A, Xu, C, Myint, S.S, Davies, J.O.J, Goh, J.Y, Loh, G, Tan, B.C, Rozen, S.G, Yu, Q, Tan, I.B.H, Cheng, C.W.S, Li, S, Chang, K.T.E, Tan, P.H, Silver, D.L, Lezhava, A, Steger, G, Hughes, J.R, Teh, B.T, Tan, P (2017). VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma. Cancer Discovery 7 (11) : 1284-1305. ScholarBank@NUS Repository.
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 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-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. © 2017 American Association for Cancer Research.
Source Title: Cancer Discovery
ISSN: 2159-8274
DOI: 10.1158/2159-8290.CD-17-0375
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