title: Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle.
abstract: The vicious cycle established between bone-associated tumours and bone resorption is the central problem with therapeutic strategies against primary bone tumours and bone metastasis. Here we report data to support inhibition of BET bromodomain proteins as a promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a BET bromodomain inhibitor, reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation both in vitro and in vivo. These effects are associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibits osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicate that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumour development.
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France [3].
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France [3] Nantes University Hospital, 1 Rue Gaston Veil, Nantes 44035, France [4].
authors.forename: Marc
authors.initials: M
authors.lastname: Baud'huin
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Lidia
authors.initials: L
authors.lastname: Rodriguez Calleja
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Jacques
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Berreur
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rédini
authors.affiliation: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII-55, Pamplona, Navarra 31008, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA [2] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France [3] Nantes University Hospital, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: 1] INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil, Nantes 44035, France [2] Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, Nantes 44035, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ory
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins