BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition.
BET Proteins Exhibit Transcriptional and Functional Opposition in the Epithelial-to-Mesenchymal Transition.
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DOI：
10.1158/1541-7786.mcr-17-0568
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Denis GV
中科院分区：
文献类型：
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作者：
Andrieu GP;Denis GV
胚胎发生和癌症中的转录程序，如上皮-间质转化（EMT），确保了细胞的可塑性，这是癌症进展的一个基本特征。作为信号转导的效应器，溴域和外端（BET）蛋白非常适合支持可塑性，因为它们作为哺乳动物转录组的共激活或共抑制因子。在这里，使用激素敏感和三阴性乳腺癌（TNBC）模型系统，我们通过操纵单个BET蛋白系统地改变了EMT的转录谱，发现BRD2积极调节EMT，而BRD3和BRD4抑制该程序。单个BET蛋白的敲除揭示了彼此不同的独立转录网络，以及与小分子泛BET抑制剂JQ1不同的转录网络，JQ1之前被错误地断言为brd4选择性。可用的小分子泛β - β抑制剂，在癌症临床试验中作为抗增殖药物，掩盖了这些生物学差异。转录谱分析显示，单独抑制的单个BET蛋白通过独特的过程参与和控制EMT。
Transcriptional programs in embryogenesis and cancer, such as the epithelial-to-mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support plasticity because they function as co-activators or co-repressors of mammalian transcriptomes. Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program. Knockdown of individual BET proteins revealed independent transcriptional networks that differed from each other and from the small-molecule pan-BET inhibitor JQ1, which previously had been misleadingly asserted to be BRD4-selective. Available small-molecule pan-BET inhibitors, proposed as anti-proliferative agents in cancer clinical trials, obscure these biological differences. Transcriptional profiling reveals that individual BET proteins, inhibited separately, engage in and control EMT through unique processes.