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DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4.
Jin, Xin; Yan, Yuqian; Wang, Dejie; Ding, Donglin; Ma, Tao; Ye, Zhenqing; Jimenez, Rafael; Wang, Liguo; Wu, Heshui; Huang, Haojie.
Affiliation
  • Jin X; Department 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.
  • Yan Y; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Wang D; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Ding D; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Ma T; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Ye Z; Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Jimenez R; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Wang L; Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • Wu H; Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: heshuiwu@hust.edu.cn.
  • Huang H; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: hua
Mol Cell ; 71(4): 592-605.e4, 2018 08 16.
Article in En | MEDLINE | ID: mdl-30057199
ABSTRACT
The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.
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Full text: 1 Database: MEDLINE Main subject: Endopeptidases / Transcription Factors / Nuclear Proteins / Gene Expression Regulation, Neoplastic / Cyclin-Dependent Kinase 4 / Cyclin-Dependent Kinase 6 / Prostatic Neoplasms, Castration-Resistant Type of study: Prognostic_studies Language: En Year: 2018 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Endopeptidases / Transcription Factors / Nuclear Proteins / Gene Expression Regulation, Neoplastic / Cyclin-Dependent Kinase 4 / Cyclin-Dependent Kinase 6 / Prostatic Neoplasms, Castration-Resistant Type of study: Prognostic_studies Language: En Year: 2018 Type: Article