DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4.
DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4.
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DUB3 通过去泛素化 BRD4 促进 BET 抑制剂耐药性和癌症进展
DOI：
10.1016/j.molcel.2018.06.036
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发表时间：
2018-08-16
期刊：
影响因子：
16
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Jin X;Yan Y;Wang D;Ding D;Ma T;Ye Z;Jimenez R;Wang L;Wu H;Huang H
溴结构域和额外末端结构域 (BET) 蛋白 BRD4 正在成为一种有前景的抗癌治疗靶点。然而，对 BET 抑制剂的耐药性经常发生，并且与癌症中 BRD4 蛋白的异常降解有关。在这里，我们证明去泛素酶 DUB3 与 BRD4 结合并促进其去泛素化和稳定。 DUB3 的表达受到 NCOR2-HDAC10 复合物的转录抑制。 NCOR2 基因在去势抵抗性前列腺癌患者标本中经常被删除，NCOR2 的缺失会导致癌细胞中 DUB3 和 BRD4 蛋白的升高。 DUB3 丰富的前列腺癌细胞在体外和小鼠体内对 BET 抑制剂 JQ1 具有耐药性，但这种效果会被 DUB3 抑制剂（例如 CDK4/6 抑制剂）以不依赖 RB 的方式减弱。我们的研究结果确定了一种先前未被识别的导致 BRD4 上调和耐药性的机制，表明 DUB3 是克服癌症中 BET 抑制剂耐药性的可行治疗靶点。 BRD4 蛋白表达增加与 BET 抑制剂耐药性有关。金等人。将 DUB3 鉴定为 BRD4 的去泛素化酶，并证明 DUB3 的异常表达通过促进 BRD4 蛋白去泛素化和稳定而赋予癌细胞 BET 抑制剂耐药性，而 CDK4/6 抑制剂可以克服这一问题。
The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by the DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer. Increased expression of BRD4 protein has been linked to BET inhibitor resistance. Jin et al. identify DUB3 as a deubiquitinase of BRD4 and demonstrate that aberrant expression of DUB3 confers BET inhibitor resistance in cancer cells by promoting BRD4 protein deubiquitination and stabilization, which can be overcome by CDK4/6 inhibitor.
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