1. Academic Validation
  2. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

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

  • Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2961-2966. doi: 10.1073/pnas.1814742116.
Xiaowei Wu 1 Qingyu Luo 1 Pengfei Zhao 1 Wan Chang 1 Yating Wang 2 Tong Shu 2 Fang Ding 1 Bin Li 2 Zhihua Liu 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China.
  • 2 Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China.
  • 3 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China; [email protected]
Abstract

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.

Keywords

DUB3; MCL1; MGMT; chemoresistance; ovarian cancer.

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