Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
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DOI：
10.1038/ncomms4511
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发表时间：
2014-03-01
影响因子：
16.6
通讯作者：
Ory, Benjamin
中科院分区：
文献类型：
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作者：
Lamoureux, Francois;Baud'huin, Marc;Ory, Benjamin
骨相关肿瘤和骨吸收之间建立的恶性循环是针对原发性骨肿瘤和骨转移的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希望的治疗策略，同时针对恶性循环的三个伙伴。JQ1是一种BET溴结构域抑制剂，在体外和体内均可降低骨肉瘤细胞的活力，抑制成骨细胞分化。这些效应与MYC和RUNX2的转录沉默有关，这是由于BRD4从它们各自的位点上缺失造成的。此外，JQ1还通过干扰brd4依赖性的NFATC1转录的RANKL激活来抑制破骨细胞分化。总的来说，我们的数据表明JQ1是成骨细胞和破骨细胞分化以及骨肿瘤发展的有效抑制剂。
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.