title: Targeting the EWSR1-FLI1 oncogene-induced protein kinase PKC-β abolishes ewing sarcoma growth.
abstract: Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma.
authors.affiliation: Institut Curie, INSERM U830, Unité de Génétique et Biologie des Cancers, Institut Curie, Unité de génétique somatique, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Surdez
authors.forename: Magdalena
authors.initials: M
authors.lastname: Benetkiewicz
authors.forename: Virginie
authors.initials: V
authors.lastname: Perrin
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Han
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Stelly
authors.initials: S
authors.lastname: Ballet
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.forename: Anne-Valérie
authors.initials: AV
authors.lastname: Decouvelaere
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos-Dubus
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.forename: Gonzague
authors.initials: G
authors.lastname: de Pinieux
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D064546:Protein Kinase C beta; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; C576197:EWSR1-FLI1 fusion protein, human; D006657:Histones; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta