title: ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers.
abstract: ARID1A (BAF250A) promotes the formation of SWI/SNF chromatin remodeling complexes containing BRG1 or BRM. It has emerged as a candidate tumor suppressor based on its frequent mutations in ovarian clear cell and endometrioid cancers and in uterine endometrioid carcinomas. Here, we report that restoring wild-type ARID1A expression in ovarian cancer cells that harbor ARID1A mutations is sufficient to suppress cell proliferation and tumor growth in mice, whereas RNA interference-mediated silencing of ARID1A in nontransformed epithelial cells is sufficient to enhance cellular proliferation and tumorigenicity. Gene expression analysis identified several downstream targets of ARID1A including CDKN1A and SMAD3, which are well-known p53 target genes. In support of the likelihood that p53 mediates the effects of ARID1A on these genes, we showed that p53 was required and sufficient for their regulation by ARID1A. Furthermore, we showed that CDKN1A (encoding p21) acted in part to mediate growth suppression by ARID1A. Finally, we obtained evidence that the ARID1A/BRG1 complex interacted directly with p53 and that mutations in the ARID1A and TP53 genes were mutually exclusive in tumor specimens examined. Our results provide functional evidence in support of the hypothesis that ARID1A is a bona fide tumor suppressor that collaborates with p53 to regulate CDKN1A and SMAD3 transcription and tumor growth in gynecologic cancers.
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Bin
authors: B
authors: Guan
authors: Tian-Li
authors: TL
authors: Wang
authors: Ie-Ming
authors: IeM
authors: Shih
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004265:DNA Helicases / Q000502:physiology*; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000637:transplantation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005816:Genetic Complementation Test; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D051900:Smad3 Protein / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; C084108:SMARCA4 protein, human; D004265:DNA Helicases