GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer
GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer
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DOI：
10.1158/1541-7786.mcr-18-1121
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发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
Johnson, Gary L.
中科院分区：
文献类型：
--
作者：
Bevill, Samantha M.;Olivares-Quintero, Jose F.;Johnson, Gary L.
靶向激酶和表观遗传调节剂的抑制剂文库的筛选鉴定了在三阴性乳腺癌（TNBC）中与末端外结构域（BET）布罗莫结构域（BD）抑制剂（JQ 1，OTX 015）具有抗增殖协同作用的几种分子。GSK 2801（模仿开关染色质重塑复合物的BAZ 2A/B BD的抑制剂）和SWI/SNF复合物的BRD 9显示出协同作用，其独立于BRD 4对P-TEF B介导的RNA聚合酶II的暂停释放的控制。在ETS调节基因的启动子/增强子处用GSK 2801或RNAi敲低BAZ 2A/B，用JQ 1选择性地置换BRD 2。BRD 2从核仁中rDNA的额外置换与45 S rRNA的减少相一致，揭示了BRD 2在调节RNA聚合酶I转录中的功能。在2D培养物中，通过组合药物处理增强BRD 2从染色质的置换诱导衰老。在球状体培养物中，联合治疗诱导了肿瘤细胞凋亡特征性的切割的半胱天冬酶-3和切割的PARP。因此，GSK 2801块BRD 2驱动的转录与BET抑制剂组合，并诱导TNBC.Implications的凋亡：协同抑制BDs编码的BAZ 2A/B，BRD 9和BET蛋白诱导TNBC细胞凋亡的核糖体DNA转录和ETS调节基因的组合抑制。
Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast cancer (TNBC). GSK2801, an inhibitor of BAZ2A/B BDs, of the imitation switch chromatin remodeling complexes, and BRD9, of the SWI/SNF complex, demonstrated synergy independent of BRD4 control of P-TEFb-mediated pause-release of RNA polymerase II. GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. Additional displacement of BRD2 from rDNA in the nucleolus coincided with decreased 45S rRNA, revealing a function of BRD2 in regulating RNA polymerase I transcription. In 2D cultures, enhanced displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induced cleaved caspase-3 and cleaved PARP characteristic of apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC.Implications: Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.