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

  • Cell Rep. 2024 Jul 23;43(7):114431. doi: 10.1016/j.celrep.2024.114431.
Yanquan Zhang  1 ,  Ka-Wing Fong  2 ,  Fengyi Mao  3 ,  Ruixin Wang  3 ,  Derek B Allison  4 ,  Dana Napier  5 ,  Daheng He  6 ,  Jinpeng Liu  6 ,  Yeqing Zhang  7 ,  Jing Chen  8 ,  Yifan Kong  3 ,  Chaohao Li  3 ,  Guangbing Li  9 ,  Jinghui Liu  2 ,  Zhiguo Li  2 ,  Haining Zhu  8 ,  Chi Wang  6 ,  Xiaoqi Liu  10
Affiliations
  • 1. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: [email protected].
  • 2. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
  • 3. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA.
  • 4. Pathology & Laboratory Medicine, University of Kentucky, Lexington, KY 40508, USA.
  • 5. Biospecimen Procurement & Translational Pathology Shared Resource Facility, University of Kentucky, Lexington, KY 40536, USA.
  • 6. Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
  • 7. Department of Biology, College of Arts & Sciences, University of Kentucky, Lexington, KY 40506, USA.
  • 8. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
  • 9. Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA.
  • 10. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: [email protected].
PMID: 38968071 DOI: 10.1016/j.celrep.2024.114431
Abstract

Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate Cancer (PCa). Understanding the mechanisms of BRD4 stability could enhance the clinical response to BRD4-targeted therapy. In this study, we report that BRD4 protein levels are significantly decreased during Mitosis in a PLK1-dependent manner. Mechanistically, we show that BRD4 is primarily phosphorylated at T1186 by the CDK1/cyclin B complex, recruiting PLK1 to phosphorylate BRD4 at S24/S1100, which are recognized by the APC/CCdh1 complex for Proteasome pathway degradation. We find that PLK1 overexpression lowers SPOP mutation-stabilized BRD4, consequently rendering PCa cells re-sensitized to BRD4 inhibitors. Intriguingly, we report that sequential treatment of docetaxel and JQ1 resulted in significant inhibition of PCa. Collectively, the results support that PLK1-phosphorylated BRD4 triggers its degradation at M phase. Sequential treatment of docetaxel and JQ1 overcomes BRD4 accumulation-associated bromodomain and extra-terminal inhibitor (BETi) resistance, which may shed light on the development of strategies to treat PCa.

Keywords
APC/C(Cdh1); BET inhibitor resistance; BRD4; CP: Cancer; CP: Molecular biology; PLK1; phosphorylation; prostate cancer.
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