DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4

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. 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.