INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma
- Bingying Zhou1,2,3,12,
- Li Wang1,4,12,
- Shu Zhang5,
- Brian D. Bennett6,
- Fan He7,
- Yan Zhang8,
- Chengliang Xiong8,
- Leng Han9,
- Lixia Diao10,
- Pishun Li4,
- David C. Fargo6,
- Adrienne D. Cox2,3,11 and
- Guang Hu4
- 1State 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;
- 2Department of Pharmacology,
- 3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- 4Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
- 5Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China;
- 6Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA;
- 7Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;
- 8Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;
- 9Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA;
- 10Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 11Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- Corresponding authors: hug4{at}niehs.nih.gov, wangl{at}pumc.edu.cn, adrienne_cox{at}med.unc.edu
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↵12 These authors contributed equally to this work.
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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.277178.115.
- Received December 31, 2015.
- Accepted May 23, 2016.
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