DUB3 promotes BET inhibitor resistance and cancer progression through deubiquitinating BRD4. Jin et al

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 the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by 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 that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.

溴结构域与额外末端结构域（bromodomain and extra-terminal domain, BET）蛋白BRD4正成为极具潜力的抗肿瘤治疗靶点。然而，BET抑制剂耐药现象频发，且该耐药与癌症中BRD4蛋白的异常降解密切相关。本研究证实，去泛素化酶DUB3可结合BRD4，促进其去泛素化修饰并稳定其蛋白水平。NCOR2-HDAC10复合物可在转录水平抑制DUB3的表达。在去势抵抗性前列腺癌患者的临床标本中，NCOR2基因常发生缺失；而NCOR2的缺失会导致癌细胞内DUB3与BRD4蛋白水平显著升高。表达功能性DUB3的前列腺癌细胞在体外及小鼠模型中均对BET抑制剂JQ1产生耐药性，但该耐药效应可被CDK4/6抑制剂等DUB3抑制剂以不依赖视网膜母细胞瘤蛋白（RB）的方式削弱。本研究揭示了此前未被阐明的BRD4蛋白上调及耐药机制，提示DUB3可作为攻克癌症中BET抑制剂耐药问题的有效治疗靶点。