title: Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors.
abstract: Emerging evidence demonstrates that subunits of the SWI/SNF chromatin remodeling complex are specifically mutated at high frequency in a variety of human cancer types. SNF5 (SMARCB1/INI1/BAF47), a core subunit of the SWI/SNF complex, is inactivated in the vast majority of rhabdoid tumors (RT), an aggressive type of pediatric cancer. SNF5-deficient cancers are diploid and genomically stable, suggesting that epigenetically based changes in transcription are key drivers of tumor formation caused by SNF5 loss. However, there is limited understanding of the target genes that drive cancer formation following SNF5 loss. Here we performed comparative expression analyses upon three independent SNF5-deficient cancer data sets from both human and mouse and identify downregulation of the BIN1 tumor suppressor as a conserved event in primary SNF5-deficient cancers. We show that SNF5 recruits the SWI/SNF complex to the BIN1 promoter, and that the marked reduction of BIN1 expression in RT correlates with decreased SWI/SNF occupancy. Functionally, we demonstrate that re-expression of BIN1 specifically compromises the proliferation of SNF5-deficient RT cell lines. Identification of BIN1 as a SNF5 target gene reveals a novel tumor suppressive regulatory mechanism whose disruption can drive cancer formation.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: McKenna
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tillman
authors.forename: E Lorena
authors.initials: EL
authors.lastname: Mora-Blanco
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Sansam
authors.forename: Edward C
authors.initials: EC
authors.lastname: Koellhoffer
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D018335:Rhabdoid Tumor / Q000378:metabolism / Q000473:pathology; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins