title: The ablation of EZH2 uncovers its crucial role in rhabdomyosarcoma formation.
abstract: Rhabdomyosarcoma (RMS) is a pediatric tumor that arises from muscle precursor cells. RMS cells express several markers of early myogenic differentiation, but they fail to complete both differentiation program and cell cycle arrest, resulting in uncontrolled proliferation and incomplete myogenesis. Previous studies showed that EZH2, which is involved in both differentiation and cancer progression, is overexpressed in RMS, but a functional binding between its expression and its functional role in tumor formation or progression has not yet been demonstrated. We hypothesized that EZH2 is a key regulator of muscular differentiation program in RMS cells.   In this study, we demonstrated that EZH2 directly binds muscle specific genes in RD cells. Silencing of EZH2 promotes the recruitment of a multiprotein complex at muscle-specific promoters, their transcriptional activation and protein expression. Moreover, we demonstrated that EZH2 is directly involved in transcriptional repression of MyoD, the main factor promoting myogenesis. EZH2 ablation induces MyoD activation the recovery of its binding on muscle-specific genes.
authors.affiliation: Department of Biomedical Sciences, Division of Biochemistry and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Marchesi
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Fiorentino
authors.forename: Flavio
authors.initials: F
authors.lastname: Rizzolio
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Luigi
authors.initials: L
authors.lastname: Bagella
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002648:Child; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus; D051379:Mice; D019042:Muscle Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics* / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2