Yao, Xiaosai, Tan, Jing, Lim, Kevin Junliang, Koh, Joanna, Ooi, Wen Fong, Li, Zhimei, Huang, Dachuan, Xing, Manjie, Chan, Yang Sun, Qu, James Zhengzhong, Tay, Su Ting, Wijaya, Giovani, Lam, Yue Ning, Hong, Jing Han, Lee-Lim, Ai Ping, Guan, Peiyong ORCID: 0000-0001-9958-0137, Ng, Michelle Shu Wen, He, Cassandra Zhengxuan, Lin, Joyce Suling, Nandi, Tannistha, Qamra, Aditi, Xu, Chang, Myint, Swe Swe, Davies, James O. J., Goh, Jian Yuan, Loh, Gary, Tan, Bryan C., Rozen, Steven G., Yu, Qiang ORCID: 0000-0003-2132-8278, Tan, Iain Bee Huat, Cheng, Christopher Wai Sam, Li, Shang, Chang, Kenneth Tou En, Tan, Puay Hoon, Silver, David Lawrence, Lezhava, Alexander, Steger, Gertrud, Hughes, Jim R., Teh, Bin Tean and Tan, Patrick (2017). VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma. Cancer Discov., 7 (11). S. 1284 - 1306. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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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 HIF2 alpha-HIF1 beta 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 HIF2 alpha and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. (C) 2017 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Yao, XiaosaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, JingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Kevin JunliangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koh, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ooi, Wen FongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, ZhimeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, DachuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xing, ManjieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Yang SunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Qu, James ZhengzhongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tay, Su TingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wijaya, GiovaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lam, Yue NingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hong, Jing HanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee-Lim, Ai PingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guan, PeiyongUNSPECIFIEDorcid.org/0000-0001-9958-0137UNSPECIFIED
Ng, Michelle Shu WenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
He, Cassandra ZhengxuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, Joyce SulingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nandi, TannisthaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Qamra, AditiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xu, ChangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Myint, Swe SweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davies, James O. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goh, Jian YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loh, GaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Bryan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rozen, Steven G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, QiangUNSPECIFIEDorcid.org/0000-0003-2132-8278UNSPECIFIED
Tan, Iain Bee HuatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheng, Christopher Wai SamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, ShangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang, Kenneth Tou EnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Puay HoonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silver, David LawrenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lezhava, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steger, GertrudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hughes, Jim R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teh, Bin TeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-212719
DOI: 10.1158/2159-8290.CD-17-0375
Journal or Publication Title: Cancer Discov.
Volume: 7
Number: 11
Page Range: S. 1284 - 1306
Date: 2017
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2159-8290
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TUMOR-SUPPRESSOR PROTEIN; HYPOXIA-INDUCIBLE FACTOR-1; TRANSCRIPTION FACTORS; TARGETED THERAPY; SUPER-ENHANCERS; GENE-EXPRESSION; HIF-BINDING; CHIP-SEQ; IDENTIFICATION; REVEALSMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21271

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