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Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation

Yanquan Zhang1, Ka-Wing Fong1, Fengyi Mao2

  • 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.

Cell Reports
|July 5, 2024
PubMed

Insights

Bromodomain-containing protein 4 (BRD4) is degraded during mitosis via PLK1-dependent phosphorylation, a key mechanism for prostate cancer therapy. This finding aids in overcoming resistance to BRD4 inhibitors when combined with docetaxel.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Bromodomain-containing protein 4 (BRD4) is a therapeutic target in prostate cancer (PCa).
  • Understanding BRD4 stability mechanisms can improve BRD4-targeted therapy efficacy.
  • BRD4 protein levels fluctuate during the cell cycle, impacting treatment response.

Purpose of the Study:

  • To elucidate the mechanisms regulating BRD4 protein stability during mitosis.
  • To investigate the role of Polo-like kinase 1 (PLK1) in BRD4 degradation.
  • To explore therapeutic strategies combining chemotherapy and BRD4 inhibitors for prostate cancer.

Main Methods:

  • Investigated BRD4 protein levels during mitosis.
  • Utilized phosphorylation site mapping and protein degradation assays.
  • Employed cell-based assays to assess the effects of PLK1, CDK1/cyclin B, and APC/CCdh1 on BRD4.
  • Tested sequential treatment of docetaxel and JQ1 in PCa models.

Main Results:

  • BRD4 protein levels significantly decrease during mitosis in a PLK1-dependent manner.
  • CDK1/cyclin B phosphorylates BRD4 at T1186, recruiting PLK1 for further phosphorylation at S24/S1100.
  • Phosphorylated BRD4 is recognized by the APC/CCdh1 complex, leading to proteasomal degradation.
  • PLK1 overexpression reduces SPOP mutation-stabilized BRD4, sensitizing PCa cells to BRD4 inhibitors.
  • Sequential treatment with docetaxel and JQ1 significantly inhibited PCa growth.

Conclusions:

  • PLK1-mediated phosphorylation of BRD4 triggers its degradation during M phase.
  • This degradation pathway is crucial for regulating BRD4 levels in prostate cancer cells.
  • Combining docetaxel and JQ1 overcomes resistance to bromodomain and extra-terminal inhibitor (BETi) therapies.
  • These findings offer insights for developing novel therapeutic strategies for prostate cancer.
Keywords:
APC/C(Cdh1)BET inhibitor resistanceBRD4CP: CancerCP: Molecular biologyPLK1phosphorylationprostate cancer

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