BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.
BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.
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DOI：
10.1016/j.celrep.2017.12.078
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发表时间：
2018-01-16
期刊：
影响因子：
8.8
通讯作者：
Mani RS
中科院分区：
文献类型：
--
作者：
Li X;Baek G;Ramanand SG;Sharp A;Gao Y;Yuan W;Welti J;Rodrigues DN;Dolling D;Figueiredo I;Sumanasuriya S;Crespo M;Aslam A;Li R;Yin Y;Mukherjee B;Kanchwala M;Hughes AM;Halsey WS;Chiang CM;Xing C;Raj GV;Burma S;de Bono J;Mani RS
BRD4属于染色质阅读器蛋白的布罗莫结构域和末端外（BET）家族，其结合乙酰化组蛋白并调节基因表达。BET抑制剂（BETi）对BRD4的药理学抑制已经表明了针对多种癌症类型的抗肿瘤活性。我们发现，BRD4是必不可少的DNA双链断裂（DSB）的修复和介导的致癌基因重排的形成，通过从事非同源末端连接（NHEJ）途径。从机制上讲，全基因组DNA断裂与组蛋白H4的乙酰化增强相关，导致BRD4募集和DNA修复复合物的稳定建立。为了支持这一点，我们还表明，在临床肿瘤样本中，BRD4蛋白水平与前列腺癌（PCa）放射治疗后的结果呈负相关。因此，除了调节基因表达外，BRD4也是DNA DSB修复的核心参与者，对癌症治疗具有重要意义。BRD4的经典功能是调节基因表达。Li等人提出的实验和临床数据表明，BRD4也是DNA修复的关键参与者，并与放射治疗后CRPC的发展相关。
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy. The classic function of BRD4 is to regulate gene expression. Li et al. present experimental and clinical data to suggest that BRD4 is also a key player in DNA repair and is associated with the development of CRPC after radiation therapy.
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影响因子：
30.8
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
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Mann, Matthias
影响因子：
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选择性抑制BET溴结构域。
影响因子：
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影响因子：
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作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network