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

Chemoresistance is a severe outcome among patients with ovarian Cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the Bcl-2 Family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian Cancer. Here, we found that deubiquitinating Enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian Cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O⁶-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 both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian Cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian Cancer.