Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Cell Rep. 2024 Jul 23;43(7):114431. doi: 10.1016/j.celrep.2024.114431. Epub 2024 Jul 4.
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/C 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.
溴结构域蛋白 4（BRD4）已成为前列腺癌（PCa）有前途的治疗靶点。了解 BRD4 稳定性的机制可以增强对 BRD4 靶向治疗的临床反应。在这项研究中，我们报告 BRD4 蛋白水平在有丝分裂过程中显著降低，这是一种依赖于 PLK1 的方式。从机制上讲，我们表明 BRD4 主要被 CDK1/周期蛋白 B 复合物在 T1186 处磷酸化，招募 PLK1 在 S24/S1100 处磷酸化 BRD4，这被 APC/C 复合物识别，用于蛋白酶体途径降解。我们发现 PLK1 的过表达降低了 SPOP 突变稳定的 BRD4，从而使 PCa 细胞对 BRD4 抑制剂重新敏感。有趣的是，我们报告说，多西紫杉醇和 JQ1 的序贯治疗导致 PCa 显著抑制。总的来说，结果支持 PLK1 磷酸化的 BRD4 在 M 期触发其降解。多西紫杉醇和 JQ1 的序贯治疗克服了 BRD4 积累相关溴结构域和末端额外抑制剂（BETi）耐药性，这可能为治疗 PCa 策略的发展提供了启示。
