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

Publication ,  Journal Article
Yao, X; Tan, J; Lim, KJ; Koh, J; Ooi, WF; Li, Z; Huang, D; Xing, M; Chan, YS; Qu, JZ; Tay, ST; Wijaya, G; Lam, YN; Hong, JH; Lee-Lim, AP ...
Published in: Cancer Discov
November 2017

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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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

November 2017

Volume

7

Issue

11

Start / End Page

1284 / 1305

Location

United States

Related Subject Headings

  • p300-CBP Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Transcription Factors
  • Regulatory Sequences, Nucleic Acid
  • Promoter Regions, Genetic
  • Oncogenes
  • Mutation
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Enhancer Elements, Genetic
 

Citation

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Yao, X., Tan, J., Lim, K. J., Koh, J., Ooi, W. F., Li, Z., … Tan, P. (2017). VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma. Cancer Discov, 7(11), 1284–1305. https://doi.org/10.1158/2159-8290.CD-17-0375
Yao, Xiaosai, Jing Tan, Kevin Junliang Lim, Joanna Koh, Wen Fong Ooi, Zhimei Li, Dachuan Huang, et al. “VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma.Cancer Discov 7, no. 11 (November 2017): 1284–1305. https://doi.org/10.1158/2159-8290.CD-17-0375.
Yao X, Tan J, Lim KJ, Koh J, Ooi WF, Li Z, et al. VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma. Cancer Discov. 2017 Nov;7(11):1284–305.
Yao, Xiaosai, et al. “VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma.Cancer Discov, vol. 7, no. 11, Nov. 2017, pp. 1284–305. Pubmed, doi:10.1158/2159-8290.CD-17-0375.
Yao X, Tan J, Lim KJ, Koh J, Ooi WF, Li Z, Huang D, Xing M, Chan YS, Qu JZ, Tay ST, Wijaya G, Lam YN, Hong JH, Lee-Lim AP, Guan P, Ng MSW, He CZ, Lin JS, Nandi T, Qamra A, Xu C, Myint SS, Davies JOJ, Goh JY, Loh G, Tan BC, Rozen SG, Yu Q, Tan IBH, Cheng CWS, Li S, Chang KTE, Tan PH, Silver DL, Lezhava A, Steger G, Hughes JR, Teh BT, Tan P. VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma. Cancer Discov. 2017 Nov;7(11):1284–1305.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

November 2017

Volume

7

Issue

11

Start / End Page

1284 / 1305

Location

United States

Related Subject Headings

  • p300-CBP Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Transcription Factors
  • Regulatory Sequences, Nucleic Acid
  • Promoter Regions, Genetic
  • Oncogenes
  • Mutation
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Enhancer Elements, Genetic