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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

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DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4

Xin Jin1, Yuqian Yan2, Dejie Wang2

  • 1Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Molecular Cell
|July 31, 2018
PubMed

Insights

Drug resistance in cancer can occur due to increased bromodomain and extra-terminal domain (BET) protein BRD4. The deubiquitinase DUB3 stabilizes BRD4, leading to resistance against BET inhibitors like JQ1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, are key therapeutic targets in cancer treatment.
  • Acquired resistance to BET inhibitors is a significant clinical challenge, often associated with dysregulation of target proteins.

Purpose of the Study:

  • To elucidate the mechanism underlying BRD4 stabilization and its role in mediating resistance to BET inhibitors.
  • To identify novel therapeutic targets for overcoming BET inhibitor resistance in cancer.

Main Methods:

  • Investigated the interaction between deubiquitinase DUB3 and BRD4 using biochemical assays.
  • Analyzed the transcriptional regulation of DUB3 by the NCOR2-HDAC10 complex.
  • Assessed the impact of NCOR2 gene deletion on DUB3 and BRD4 protein levels in prostate cancer cells.
  • Evaluated the sensitivity of DUB3-proficient cancer cells to the BET inhibitor JQ1 in vitro and in vivo models.
  • Tested the efficacy of DUB3 inhibitory agents, including CDK4/6 inhibitors, in overcoming BET inhibitor resistance.

Main Results:

  • Demonstrated that DUB3 binds to and deubiquitinates BRD4, thereby stabilizing the protein.
  • Showed that DUB3 expression is transcriptionally repressed by the NCOR2-HDAC10 complex.
  • Observed frequent deletion of the NCOR2 gene in castration-resistant prostate cancer, leading to elevated DUB3 and BRD4 levels.
  • Found that DUB3-expressing prostate cancer cells exhibit resistance to the BET inhibitor JQ1.
  • Confirmed that DUB3 inhibitory agents can diminish JQ1 resistance in a RB-independent manner.

Conclusions:

  • Identified a novel mechanism involving DUB3-mediated BRD4 stabilization that contributes to BET inhibitor resistance.
  • Highlighted the NCOR2 gene deletion as a potential biomarker for BET inhibitor resistance.
  • Positioned DUB3 as a promising therapeutic target to overcome resistance to BRD4-targeting anticancer drugs.
Keywords:
BET inhibitorBRD4CDK4/6 inhibitorDUB3HDAC10NCOR2SPOPcancerdeubiquitinationdrug resistance

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