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MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer
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MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer
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Journal Article
MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer
2019
Overview
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.
Publisher
National Academy of Sciences
Subject
/ Cancer
/ DNA
/ DNA Modification Methylases - genetics
/ DNA Repair Enzymes - genetics
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Gene Expression Regulation, Neoplastic - drug effects
/ Histone Deacetylase Inhibitors - pharmacology
/ Humans
/ Myeloid Cell Leukemia Sequence 1 Protein - genetics
/ O6-methylguanine-DNA methyltransferase
/ Ovarian Neoplasms - drug therapy
/ Ovarian Neoplasms - genetics
/ Ovarian Neoplasms - pathology
