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

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VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
Title:
VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
Journal Title:
Cancer Discovery
Keywords:
Publication Date:
12 September 2017
Citation:
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 Discovery, 7(11), 1284–1305. doi:10.1158/2159-8290.cd-17-0375
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. Cancer Discov; 7(11); 1284–305. ©2017 AACR.
License type:
Publisher Copyright
Funding Info:
This work was supported by Biomedical Research Council Young Investigator Grant 1510851024, National Natural Science Foundation of China 61661146004, National Research Foundation grant NRF2016NRF-NSFC001-057, and National Medical Research Council grants NMRC/STaR/0026/2015, NMRC/STAR/0024/2014, NMRC/CIRG/1402/2014, and NMRC/CBRG/069/2014. Core funding was provided by the Genome Institute of Singapore and Institute of Molecular and Cell Biology under the Agency for Science, Technology and Research, and Duke-NUS Medical School. Other sources of support include the Cancer Science Institute of Singapore, NUS, funded by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and Biomedical Research Council Strategic Positioning Fund 2012/001. J.R. Hughes was supported by a Wellcome Trust Strategic Award (reference 106130/Z/14/Z) and Medical Research Council (MRC) Core funding. J.O.J. Davies was funded by a Wellcome Trust Clinical Research Training Fellowship (ref 098931/Z/12/Z). We thank Hui Hoon Chua, Angie Tan, and Liang Kai Koh for their administrative support. We thank the Sequencing and Scientific Computing teams at the Genome Institute of Singapore for sequencing services and data management capabilities, and the Duke-NUS Genome Biology Facility for sequencing services. We thank the Advanced Molecular Pathology Laboratory of the Institute of Molecular and Cell Biology for pathology evaluation. Xiaosai Yao dedicates this paper to the memory of her mother, Tan Limin, for her unconditional love and support. This work was supported by core funding from the Genome Institute of Singapore and Institute of Molecular and Cell Biology under the Agency for Science, Technology and Research, Biomedical Research Council Young Investigator Grant 1510851024, National Medical Research Council grants NMRC/STaR/0026/2015, NMRC/CIRG/1402/2014 and CBRG/069/2014, and National Research Foundation grant NRF2016NRF-NSFC001-057. Other sources of support include the Cancer Science Institute of Singapore, NUS, funded by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. J.R.H. was supported by a Wellcome Trust Strategic Award (reference 106130/Z/14/Z) and Medical Research Council (MRC) Core funding. J.O.J.D. was funded by Wellcome Trust Clinical Research Training Fellowship (ref 098931/Z/12/Z).
Description:
Please find the link to the article at the publisher's URL: http://dx.doi.org/10.1158/2159-8290.cd-17-0375
ISSN:
2159-8290
2159-8274
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