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].
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].
Nat Commun. 2014 Mar 19;5:3511. doi: 10.1038/ncomms4511.
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.
骨相关肿瘤与骨吸收之间建立的恶性循环是原发性骨肿瘤和骨转移治疗策略的核心问题。在这里，我们报告的数据支持抑制 BET 溴结构域蛋白作为一种有前途的治疗策略，该策略同时针对恶性循环的三个合作伙伴。BET 溴结构域抑制剂 JQ1 的治疗可降低骨肉瘤细胞的活力，并在体外和体内抑制成骨细胞分化。这些作用与 MYC 和 RUNX2 的转录沉默相关，这是由于 BRD4 从它们各自的位置耗尽所致。此外，JQ1 还通过干扰 BRD4 依赖性 RANKL 激活 NFATC1 转录来抑制破骨细胞分化。总的来说，我们的数据表明 JQ1 是一种有效的成骨细胞和破骨细胞分化以及骨肿瘤发展的抑制剂。
