DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4

Mol Cell. 2018 Aug 16;71(4):592-605.e4. doi: 10.1016/j.molcel.2018.06.036. Epub 2018 Jul 26.

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.

Keywords: BET inhibitor; BRD4; CDK4/6 inhibitor; DUB3; HDAC10; NCOR2; SPOP; cancer; deubiquitination; drug resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Azepines / pharmacology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / genetics*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / genetics*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Male
  • Mice
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Co-Repressor 2 / deficiency
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Piperazines / pharmacology
  • Prostate / drug effects
  • Prostate / enzymology
  • Prostate / pathology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / enzymology
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Proteolysis
  • Pyridines / pharmacology
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Triazoles / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • (+)-JQ1 compound
  • Antineoplastic Agents
  • Azepines
  • BRD4 protein, human
  • Cell Cycle Proteins
  • NCOR2 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 2
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Transcription Factors
  • Triazoles
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Endopeptidases
  • USP17L2 protein, human
  • HDAC10 protein, human
  • Histone Deacetylases
  • palbociclib