title: Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation.
abstract: Collectively, genes encoding subunits of the SWI/SNF (BAF) chromatin remodeling complex are mutated in 20% of all human cancers, with the SMARCA4 (BRG1) subunit being one of the most frequently mutated. The SWI/SNF complex modulates chromatin remodeling through the activity of two mutually exclusive catalytic subunits, SMARCA4 and SMARCA2 (BRM). Here, we show that a SMARCA2-containing residual SWI/SNF complex underlies the oncogenic activity of SMARCA4 mutant cancers. We demonstrate that a residual SWI/SNF complex exists in SMARCA4 mutant cell lines and plays essential roles in cellular proliferation. Further, using data from loss-of-function screening of 165 cancer cell lines, we identify SMARCA2 as an essential gene in SMARCA4 mutant cancer cell lines. Mechanistically, we reveal that Smarca4 inactivation leads to greater incorporation of the nonessential SMARCA2 subunit into the SWI/SNF complex. Collectively, these results reveal a role for SMARCA2 in oncogenesis caused by SMARCA4 loss and identify the ATPase and bromodomain-containing SMARCA2 as a potential therapeutic target in these cancers.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Boris G
authors.initials: BG
authors.lastname: Wilson
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Helming
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.forename: Youngha
authors.initials: Y
authors.lastname: Kim
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.forename: Zainab
authors.initials: Z
authors.lastname: Jagani
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases