Significance Ovarian cancer is the leading cause of death among gynecological malignancies and has a poor prognosis characterized by resistance to chemotherapy. MCL1 has been found to play an essential role in chemoresistance and could be a promising therapeutic target. However, designing specific inhibitors targeting MCL1 remains challenging. Here, we found that deubiquitinating enzyme 3 (DUB3) stabilizes MCL1 via deubiquitination. We identified that O 6 -methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression. We further showed that histone deacetylase (HDAC) inhibitors could significantly activate MGMT/DUB3 expression to sensitize ovarian cancer cells to PaTrin-2, providing an ideal therapeutic option involving the combined treatment of HDACis and PaTrin-2 in ovarian cancer.

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer