title: INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma.
abstract: Superenhancers (SEs) are large genomic regions with a high density of enhancer marks. In cancer, SEs are found near oncogenes and dictate cancer gene expression. However, how oncogenic SEs are regulated remains poorly understood. Here, we show that INO80, a chromatin remodeling complex, is required for SE-mediated oncogenic transcription and tumor growth in melanoma. The expression of Ino80, the SWI/SNF ATPase, is elevated in melanoma cells and patient melanomas compared with normal melanocytes and benign nevi. Furthermore, Ino80 silencing selectively inhibits melanoma cell proliferation, anchorage-independent growth, tumorigenesis, and tumor maintenance in mouse xenografts. Mechanistically, Ino80 occupies >90% of SEs, and its occupancy is dependent on transcription factors such as MITF and Sox9. Ino80 binding reduces nucleosome occupancy and facilitates Mediator recruitment, thus promoting oncogenic transcription. Consistently, genes co-occupied by Ino80 and Med1 are selectively expressed in melanomas compared with melanocytes. Together, our results reveal an essential role of INO80-dependent chromatin remodeling in SE function and suggest a novel strategy for disrupting SEs in cancer treatment.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
authors.forename: Bingying
authors.initials: B
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China;
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Brian D
authors.initials: BD
authors.lastname: Bennett
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;
authors.forename: Fan
authors.initials: F
authors.lastname: He
authors.affiliation: Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;
authors.forename: Chengliang
authors.initials: C
authors.lastname: Xiong
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA;
authors.forename: Leng
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Pishun
authors.initials: P
authors.lastname: Li
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: David C
authors.initials: DC
authors.lastname: Fargo
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D056913:Mediator Complex Subunit 1 / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C494434:INO80B protein, human; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D009687:Nuclear Proteins; D014157:Transcription Factors
keywords: INO80; chromatin remodeler; oncogenic transcription; superenhancer