Lamoureux, F., Baud'huin, M., Calleja, L.R. et al. (7 more authors) (2014) Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle. NATURE COMMUNICATIONS, 5. ARTN 3511. ISSN 2041-1723
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 Nature Publishing Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Adolescent; Adult; Aged; Aged, 80 and over; Animals; Azepines; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C3H; Mice, Nude; Middle Aged; Nuclear Proteins; Osteosarcoma; Proto-Oncogene Proteins c-myc; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcription Factors; Triazoles; Xenograft Model Antitumor Assays; Young Adult |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 12 Apr 2016 13:29 |
Last Modified: | 21 Mar 2018 03:58 |
Published Version: | http://www.nature.com/ncomms/2014/140319/ncomms451... |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/ncomms4511 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:97044 |