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

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

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: yanquan.zhang@uky.edu.
  • 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: xiaoqi.liu@uky.edu.
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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