ECTS2014 Poster Presentations Cancer and bone: basic, translational and clinical (11 abstracts)
Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle
Francois Lamoureux 1, , Marc Baud’huin 1, , Lidia Rodriguez Calleja 1, , Camille Jacques 1, , Françoise Redini 1, , Fernando Lecanda 5 , James E. Bradner 3, , Dominique Heymann 1, & Benjamin Ory 1,
1INSERM UMR957, équipe labélisé Ligue 2012, Nantes, France; 2Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil, 44035 Nantes, France; 3Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston Massachusetts 02115, USA; 4Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston Massachusetts 02115, USA; 5Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
The vicious cycle established between bone associated tumors and bone resorption is the central problem with therapeutic strategies against primary bone tumors and bone metastasis. The bromodomain and extra-terminal domain (BET) protein family is an important class of ‘histone reading protein’ capable to recognize the N-acetylation of lysine residues on histone tails. BET bromain proteins have recently been described as regulators of MYC expression in various tumors. In this study, we report data to support inhibition of BET bromodomain as a novel and promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a unique BET bromodomain inhibitor, reduced cell viability and induced apoptosis in osteosarcoma cells and, inhibited osteoblastic differentiation in vitro. In vivo, BET inhibitor (IP; 50mg/kg) significantly inhibits tumor growth by 70% and prolongs survival in both POS-1 syngenic and MMNG/HOS xenograft models compared to control. Additionally, these results were accompanied by a decrease of associated bone lesions.
These effects were associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibited osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicates that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumor development.
Article tools
My recent searches
My recently viewed abstracts
Authors
Bone Abstracts
ISSN 2052-1219 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more