Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
François Lamoureux, Marc Baud'huin, Lidia Rodriguez Calleja, Camille Jacques, Martine Berreur, Françoise Rédini, Fernando Lecanda, James E Bradner, Dominique Heymann, Benjamin Ory, François Lamoureux, Marc Baud'huin, Lidia Rodriguez Calleja, Camille Jacques, Martine Berreur, Françoise Rédini, Fernando Lecanda, James E Bradner, Dominique Heymann, Benjamin Ory
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.
Source: PubMed