BRD4 and Cancer: going beyond transcriptional regulation.
BRD4 and Cancer: going beyond transcriptional regulation.
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DOI：
10.1186/s12943-018-0915-9
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发表时间：
2018-11-22
期刊：
影响因子：
37.3
通讯作者：
Ciarrocchi A
中科院分区：
文献类型：
--
作者：
Donati B;Lorenzini E;Ciarrocchi A
BRD4是溴结构域和末端外（BET）蛋白家族的成员，在癌症中由于其在超级增强子（SE）组织和癌基因表达调控中的作用而被广泛认可。BRD4的抑制缩短了SE和靶启动子之间的通信，随后细胞特异性抑制癌细胞所依赖的癌基因和细胞死亡。迄今为止，这是BET抑制剂的最可信的作用机制，BET抑制剂是一类靶向BET蛋白的小分子，目前正在几种癌症环境中进行临床试验。然而，最近的证据表明，BRD4在癌症中的相关性超出了其在转录调控中的作用，并将这种蛋白质鉴定为基因组稳定性的保持者。事实上，已经提出了BRD4在控制DNA损伤检查点激活和修复以及端粒维持中的非转录作用，为这种蛋白质的多种功能提供了新的线索，并为BETi在癌症中的应用开辟了新的视角。在这里，我们讨论了目前可用的信息BRD4的非规范，非转录功能及其在癌症生物学的影响。将这些信息与已知的BRD4在基因表达调控中的作用相结合，我们提出了一个“共同”模型来解释BRD4基因组功能。此外，鉴于BRD4的横向功能，我们对BETi的细胞毒性活性提供了新的解释，并讨论了在临床环境中广泛和集中使用这些药物的新可能性。
BRD4, member of the Bromodomain and Extraterminal (BET) protein family, is largely acknowledged in cancer for its role in super-enhancers (SEs) organization and oncogenes expression regulation. Inhibition of BRD4 shortcuts the communication between SEs and target promoters with a subsequent cell-specific repression of oncogenes to which cancer cells are addicted and cell death. To date, this is the most credited mechanism of action of BET inhibitors, a class of small molecules targeting BET proteins which are currently in clinical trials in several cancer settings. However, recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation and identifies this protein as a keeper of genome stability. Indeed, a non-transcriptional role of BRD4 in controlling DNA damage checkpoint activation and repair as well as telomere maintenance has been proposed, throwing new lights into the multiple functions of this protein and opening new perspectives on the use of BETi in cancer. Here we discuss the current available information on non-canonical, non-transcriptional functions of BRD4 and on their implications in cancer biology. Integrating this information with the already known BRD4 role in gene expression regulation, we propose a “common” model to explain BRD4 genomic function. Furthermore, in light of the transversal function of BRD4, we provide new interpretation for the cytotoxic activity of BETi and we discuss new possibilities for a wide and focused employment of these drugs in clinical settings.
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