MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer
Menée à l'aide de lignées cellulaires et d'échantillons tumoraux inclus en paraffine après prélèvement sur 150 patientes atteintes d'un cancer de l'ovaire, cette étude met en évidence un mécanisme par lequel la déubiquitinase DUB3, activée par la méthyle transférase MGMT, stabilise la protéine MCL1 et favorise la chimiorésistance des cellules cancéreuses
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 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. 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.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.