title: INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer.
abstract: Epigenetic regulators are attractive targets for the development of new cancer therapies. Among them, the ATP-dependent chromatin remodeling complexes control the chromatin architecture and have important roles in gene regulation. They are often found to be mutated and de-regulated in cancers, but how they influence the cancer gene expression program during cancer initiation and progression is not fully understood. Here we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC). Ino80, the SWI/SNF ATPase in the complex, is highly expressed in NSCLC cells compared with normal lung epithelia cells. Further, its expression, as well as that of another subunit Ino80B, negatively correlates with disease prognosis in lung cancer patients. Functionally, INO80 silencing inhibits NSCLC cell proliferation and anchorage-independent growth in vitro and tumor formation in mouse xenografts. It occupies enhancer regions near lung cancer-associated genes, and its occupancy correlates with increased genome accessibility and enhanced expression of downstream genes. Together, our study defines a critical role of INO80 in promoting oncogenic transcription and NSCLC tumorigenesis, and reveals a potential treatment strategy for inhibiting the cancer transcription network by targeting the INO80 chromatin remodeling complex.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: B
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, China.|Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Li
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Bennett
authors.affiliation: Clinical Research Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Snyder
authors.affiliation: Clinical Research Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Garantziotis
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: D 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, NC, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Cox
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hu
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D011379:Prognosis; D011485:Protein Binding; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C524421:INO80 protein, human