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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 Published OnlineFirst September 11, 2017; DOI: 10.1158/2159-8290.CD-17-0375 RESEARCH ARTICLE VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma Xiaosai Yao1,2, Jing Tan3,4, Kevin Junliang Lim5, Joanna Koh1, Wen Fong Ooi1, Zhimei Li3, Dachuan Huang3, Manjie Xing1,5,6, Yang Sun Chan1, James Zhengzhong Qu1, Su Ting Tay5, Giovani Wijaya3, Yue Ning Lam1, Jing Han Hong5, Ai Ping Lee-Lim1, Peiyong Guan3, Michelle Shu Wen Ng2, Cassandra Zhengxuan He1, Joyce Suling Lin1, Tannistha Nandi1, Aditi Qamra1,7, Chang Xu5,8, Swe Swe Myint3, James O. J. Davies9, Jian Yuan Goh1, Gary Loh1, Bryan C. Tan10, Steven G. Rozen5, Qiang Yu1, Iain Bee Huat Tan1,11, Christopher Wai Sam Cheng12, Shang Li5, Kenneth Tou En Chang13, Puay Hoon Tan14, David Lawrence Silver9, Alexander Lezhava15, Gertrud Steger16, Jim R. Hughes9, Bin Tean Teh2,3,5,8,17, and Patrick Tan1,5,8,17 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. 15-CD-17-0375_p1284-1305.indd 1284 10/23/17 2:18 PM Published OnlineFirst September 11, 2017; DOI: 10.1158/2159-8290.CD-17-0375 ABSTRACT Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been exten- sively 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 profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi edZNF395 as a ccRCC- specifi c 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-specifi c driver mutations such asVHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGNIFICANCE: Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somati- cally 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-specifi c promoter–enhancer complexes.Cancer Discov; 7(11); 1284–305. ©2017 AACR. See related commentary by Ricketts and Linehan, p. 1221. INTRODUCTION (Myc ), Vhl loss drives spontaneous ccRCC formation in mouse models ( 7–11 ). VHL encodes an E3 ubiquitin ligase ( 12, 13 ) Clear cell renal cell carcinoma (ccRCC) is the most com- that targets HIF1α (HIF1A ) and HIF2α (EPAS1 ) for degrada- mon subtype of kidney cancer, with 338,000 new cases in 2012 tion ( 14, 15 ). VHL loss in ccRCC results in constitutive activa- worldwide ( 1 ). With most ccRCCs being radiochemoresistant, tion of HIF1/2α and subsequent transactivation ( 16, 17 ) of patients with metastatic ccRCC exhibit dismal 8% fi ve-year downstream genes regulating angiogenesis, glycolysis ( 18 ), overall survival ( 2 ). Although targeted therapies inhibiting lipogenesis ( 19, 20 ), cell cycle ( 21 ), and antiapoptosis ( 22 ). angiogenesis and mTOR pathways can lead to initial tumor Most reports studying VHL/HIF transcriptional activation control, most patients develop resistance in less than a year have focused on HIF-bound promoters ( 23–28 ). However, ( 3, 4 ). A better understanding of ccRCC molecular dependen- recent evidence suggests an emerging role for distal enhancer cies and vulnerabilities is thus needed to develop new therapeu- elements in VHL/HIF transcriptional control ( 29, 30 ). For tic strategies for patients who fail standard-of-care treatment. example, HIF2α-bound distal enhancers activate the proto- Loss of the von Hippel–Lindau (VHL ) tumor suppressor oncogenes MYC ( 31 ) and CCND1 ( 21 ) and coincide with is a defi ning feature of ccRCC ( 5, 6 ). When partnered with ccRCC genetic risk alleles. Nevertheless, such studies focused inactivation of additional tumor suppressors (Pbrm1, Bap1, on individual enhancers, and the majority of distal elements Trp53, Rb1, and/or Cdkn2a ) and/or activation of oncogenes in ccRCC remain largely unexplored. 1 Cancer Therapeutics and Stratifi ed Oncology, Genome Institute of Singapore. 15 Translational Research, Genome Institute of Singapore, Singapore, Singapore. 2 Institute of Molecular and Cell Biology, Singapore. Singapore. 16 Institute of Virology, University of Cologne, Fuerst-Pueckler- 3 Laboratory of Cancer Epigenome, Department of Medical Sciences, Strasse, Cologne, Germany. 17 SingHealth/Duke-NUS Institute of Precision National Cancer Centre, Singapore. 4 State Key Laboratory of Oncology Medicine, National Heart Centre Singapore, Singapore . in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China. Note: Supplementary data for this article are available at Cancer Discovery 5 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Sin- Online (http://cancerdiscovery.aacrjournals.org/). gapore. 6 NUS Graduate School for Integrative Sciences and Engineering, X. Yao, J. Tan, and K.J. Lim contributed equally to this article. National University of Singapore, Singapore. 7 Department of Physiol- ogy, Yong Loo Lin School of Medicine, National University of Singapore, Corresponding Authors: Patrick Tan, Duke-NUS Medical School, 8 Col- Singapore. 8 Cancer Science Institute of Singapore, National University lege Road, Singapore 169857, Singapore. Phone: 65-6516-1783; Fax: of Singapore, Singapore. 9 Medical Research Council (MRC) Molecular 65-6221-2402; E-mail: [email protected] ; and Bin Tean Teh, Duke- Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford NUS Medical School , 8 College Road, Singapore 169857, Singapore. Phone: University, United Kingdom. 10 Cardiovascular and Metabolic Disorders 65-6601-1324; Fax: 65-6221-2402; E-mail: teh.bin.tean@ singhealth. Programme, Duke-NUS Medical School, Singapore. 11 Division of Medi- com.sg 12 cal Oncology, National Cancer Centre Singapore, Singapore. Depart- doi: 10.1158/2159-8290.CD-17-0375 ment of Urology, Singapore General Hospital, Singapore. 13 Department 2017 American Association for Cancer Research. of Pathology and Laboratory Medicine, KK Women’s and Children’s Hos- © pital, Singapore. 14 Department of Pathology, Singapore General Hospital, NOvember 2017 CANCER DISCOVERY | 1285 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. 15-CD-17-0375_p1284-1305.indd 1285 10/23/17 2:18 PM Published OnlineFirst September 11, 2017; DOI: 10.1158/2159-8290.CD-17-0375 RESEARCH ARTICLE Yao et al. Delineating the global ccRCC cis-regulatory landscape may Fig. S1A). Among the 10 primary ccRCCs, 9 harbored VHL also identify master regulators involved in tissue-specific mutations, detected by targeted sequencing and confirmed by disease processes. Compared with promoters that are largely Sanger sequencing (Supplementary Table S3). Cell lines 786-O cell-type invariant, distal enhancers integrate multiple line- and A-498 also harbor VHL truncating mutations (Supplemen- age- and context-dependent signals, catering to the special- tary Table S3). The VHL mutations co-occurred with somatic ized needs of diverse cell types and diseases (32, 33). In cancer, mutations of other chromatin modifiers commonly found in such master regulators are frequently located near “super- ccRCC, including PBRM1 (7/10), SETD2 (1/10), KDM5A (1/10), enhancers” or “stretch-enhancers” marked by long stretches KDM5C (1/10), ARID1A (1/10), and KMT2C (1/10). of H3K27ac signals (34, 35). For example, subtype-specific Specific histone modifications can distinguish different genomic alterations such as EGFRvIII in glioblastoma (36) categories of functional regulatory elements—H3K4me3 is and EWS–FLI in Ewing sarcoma (37) induce de novo enhanc- generally associated with promoters, H3K4me1 with enhanc- ers, causing reactivation of developmental master regula- ers, and H3K27ac with active elements (33, 43). Integrating tors required for self-renewal and lineage specification (36). signals from three histone marks and GENCODE v19 anno- Although VHL inactivation has been shown to modulate tated transcription start sites (TSS), we defined active promot- protein levels of different histone modifiers (e.g., KDM5C/ ers as H3K27ac+/H3K4me3+/±2.0 kb TSS regions, and distal JARID1C, ref. 38; HDAC1, ref. 39; JMJD1A, ref. 40; JMJD2B, enhancers as H3K27ac+/H3K4me1+ regions not overlapping ref. 40; JMJD2C, ref. 41), the impact of these protein altera- with promoters. Focusing on epigenomic events specific to tions at specific epigenomic loci remains unclear. Moreover, somatic cancer cells, we derived cell lines from five primary previous studies profiling histone modifications in ccRCCs tumors and, combined with the commercial lines, excluded have also been limited by small sample sizes (2 cases; ref. 42), peaks not found in any of the cell lines to reduce confounding
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