BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer
BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer
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BRD4 通过上调 C-MYC 调节 EZH2 转录，是膀胱癌的新治疗靶点
DOI：
10.1158/1535-7163.mct-15-0750
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发表时间：
2016-05-01
影响因子：
5.7
通讯作者：
Jiang, Guosong
中科院分区：
文献类型：
--
作者：
Wu, Xinchao;Liu, Dong;Jiang, Guosong
罹患膀胱癌的人往往会死于这种难治的疾病。目前的治疗策略有限，可能是由于潜在的分子复杂性和不充分的理解。因此，探索膀胱癌新的治疗靶点仍然是必要的。在这里，我们发现溴结构域-4蛋白(BRD4)是溴结构域和端外结构域(BET)家族成员重要表观基因组阅读器，是ZEST同源增强子2(EZH2)的关键上游调节因子，代表了膀胱癌治疗的新靶点。我们发现BRD4在膀胱癌细胞和组织中显著过表达。抑制BRD4在体外抑制膀胱癌细胞增殖的同时，伴随着细胞凋亡的积聚，在体内抑制肿瘤生长。我们进一步发现，抑制BRD4降低了EZH2的mRNA和蛋白水平，而C-MYC的异位表达则逆转了这一作用。特别是，使用shRNA或BET抑制剂JQ1单独沉默BRD4显著减少了膀胱癌中C-MYC对EZH2启动子的招募。简而言之，我们的研究表明，BRD4通过上调C-MYC来正向调节EZH2的转录，是转录程序干预这种顽固性疾病的药物治疗的一个新的有前途的靶点。摩尔癌症治疗；15(5)；1029-42。©2016 AACR。
People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (EZH2), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of BRD4 decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis in vitro and suppressed tumor growth in vivo. We further found that suppression of BRD4 decreased the mRNA and protein levels of EZH2, which was reversed by ectopic expression of C-MYC. In particular, individual silencing of BRD4 using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to EZH2 promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulates EZH2 transcription through upregulation of C-MYC, and is a novel promising target for pharmacologic treatment in transcriptional program intervention against this intractable disease. Mol Cancer Ther; 15(5); 1029–42. ©2016 AACR.