title: Targeting the epigenetic readers in Ewing sarcoma inhibits the oncogenic transcription factor EWS/Fli1.
abstract: Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults. Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease. The most common case is the translocation t (11; 22) (q24;q12) which yields the EWS-Fli1 chimeric transcription factor. Finding a way to directly target EWS-Fli1 remains a central therapeutic approach to eradicate this aggressive cancer. Here we demonstrate that treating Ewing Sarcoma cells with JQ1(+), a BET bromodomain inhibitor, represses directly EWS-Fli1 transcription as well as its transcriptional program. Moreover, the Chromatin Immuno Precipitation experiments demonstrate for the first time that these results are a consequence of the depletion of BRD4, one of the BET bromodomains protein from the EWS-Fli1 promoter. In vitro, JQ1(+) treatment reduces the cell viability, impairs the cell clonogenic and the migratory abilities, and induces a G1-phase blockage as well as a time- and a dose-dependent apoptosis. Furthermore, in our in vivo model, we observed a tumor burden delay, an inhibition of the global vascularization and an increase of the mice overall survival. Taken together, our data indicate that inhibiting the BET bromodomains interferes with EWS-FLi1 transcription and could be a promising strategy in the Ewing tumors context.
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Jacques
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.|Nantes University Hospital, Nantes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: Lidia
authors.initials: L
authors.lastname: Rodriguez Calleja
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: Institut Curie, INSERM U830, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.|Nantes University Hospital, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, UMR 957, Équipe Labellisée Ligue 2012, Nantes, France.|Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000037:antagonists & inhibitors*; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors*; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014230:Triazoles; C561695:(+)-JQ1 compound; C106031:EWS-FLI fusion protein; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
keywords: EWS/Fli1; Ewing sarcoma; JQ1; bromodomain; epigenetic