title: Failure to downregulate the BAF53a subunit of the SWI/SNF chromatin remodeling complex contributes to the differentiation block in rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and young adults, is characterized by a partially differentiated myogenic phenotype. We have previously shown that the blocking of tumor growth and resumption of differentiation can be achieved by re-expression of miR-206, a muscle-enriched microRNA missing in RMS. In this work, we focused on BAF53a, one of the genes downregulated in miR-206-expressing RMS cells, which codes for a subunit of the SWI/SNF chromatin remodeling complex. Here we show that the BAF53a transcript is significantly higher in primary RMS tumors than in normal muscle, and is a direct target of miR-206. Sustained expression of BAF53a interferes with differentiation in myogenic cells, whereas its silencing in RMS cells increases expression of myogenic markers and inhibits proliferation and anchorage-independent growth. Accordingly, BAF53a silencing also impairs embryonal RMS and alveolar RMS tumor growth, inducing their morphological and biochemical differentiation. These results indicate that failure to downregulate the BAF53a subunit may contribute to the pathogenesis of RMS, and suggest that BAF53a may represent a novel therapeutic target for this tumor.
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Taulli
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Foglizzo
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Morena
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: D M
authors.initials: DM
authors.lastname: Coda
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Ala
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bersani
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Maestro
authors.affiliation: 1] Department of Oncology, University of Turin School of Medicine, Turin, Italy [2] CERMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ponzetto
mesh_terms: D000199:Actins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D024510:Muscle Development / Q000235:genetics; D019042:Muscle Neoplasms / Q000235:genetics / Q000473:pathology*; D017570:MyoD Protein / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000473:pathology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C116160:ACTL6A protein, human; D000199:Actins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors