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Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle

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  • François Lamoureux

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil)

  • Marc Baud’huin

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil
    Nantes University Hospital, 1 Rue Gaston Veil)

  • Lidia Rodriguez Calleja

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil)

  • Camille Jacques

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil)

  • Martine Berreur

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil)

  • Françoise Rédini

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil)

  • Fernando Lecanda

    (Adhesion and Metastasis Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII-55)

  • James E. Bradner

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street
    Harvard Medical School, 25 Shattuck Street)

  • Dominique Heymann

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil
    Nantes University Hospital, 1 Rue Gaston Veil)

  • Benjamin Ory

    (INSERM, UMR 957, Équipe labellisée ligue 2012, 1 Rue Gaston Veil
    Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, 1 Rue Gaston Veil)

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.

Suggested Citation

  • François Lamoureux & Marc Baud’huin & Lidia Rodriguez Calleja & Camille Jacques & Martine Berreur & Françoise Rédini & Fernando Lecanda & James E. Bradner & Dominique Heymann & Benjamin Ory, 2014. "Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle," Nature Communications, Nature, vol. 5(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4511
    DOI: 10.1038/ncomms4511
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    Cited by:

    1. Jiahui Du & Yili Liu & Xiaolin Wu & Jinrui Sun & Junfeng Shi & Hongming Zhang & Ao Zheng & Mingliang Zhou & Xinquan Jiang, 2023. "BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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