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

Xiaowei Wu1, Qingyu Luo1, Pengfei Zhao1

  • 1State 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.

Proceedings of the National Academy of Sciences of the United States of America
|February 6, 2019
PubMed

Insights

Deubiquitinating enzyme 3 (DUB3) protects chemoresistance in ovarian cancer by stabilizing MCL1. Inhibiting the O6-methylguanine-DNA methyltransferase (MGMT)-DUB3-MCL1 axis with PaTrin-2 and HDAC inhibitors offers a promising therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Chemoresistance in ovarian cancer leads to poor patient prognosis.
  • The antiapoptotic protein MCL1 is crucial for chemoresistance and is a potential therapeutic target.

Purpose of the Study:

  • To elucidate the regulatory mechanism of MCL1 in ovarian cancer chemoresistance.
  • To identify novel therapeutic strategies targeting the identified pathway.

Main Methods:

  • Investigated the interaction between DUB3 and MCL1 in ovarian cancer cells.
  • Assessed the role of MGMT in regulating DUB3 transcription.
  • Evaluated the efficacy of PaTrin-2 and HDAC inhibitors in vitro and in vivo.

Main Results:

  • DUB3 deubiquitinates and protects MCL1 from degradation in ovarian cancer cells.
  • MGMT transcriptionally activates DUB3, forming the MGMT-DUB3-MCL1 axis.
  • PaTrin-2 suppressed ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression.
  • HDAC inhibitors activated MGMT/DUB3 expression, and their combination with PaTrin-2 yielded optimal therapeutic effects.

Conclusions:

  • The MGMT-DUB3-MCL1 axis is essential for ovarian cancer chemoresistance.
  • Combined treatment with HDAC inhibitors and PaTrin-2 effectively overcomes chemoresistance in ovarian cancer.
Keywords:
DUB3MCL1MGMTchemoresistanceovarian cancer

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