含溴结构域蛋白 4 (BRD4) 已成为前列腺癌 (PCa) 的一个有前景的治疗靶点。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期间以 PLK1 依赖性方式显着降低。从机制上讲，我们发现 BRD4 主要在 T1186 处被 CDK1/细胞周期蛋白 B 复合物磷酸化，招募 PLK1 在 S24/S1100 处磷酸化 BRD4，APC/CCdh1 复合物会识别 BRD4 进行蛋白酶体途径降解。我们发现 PLK1 过表达会降低 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，我们报告多西他赛和 JQ1 序贯治疗可显着抑制 PCa。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 积累相关的溴结构域和末端外抑制剂 (BETi) 耐药性，这可能有助于开发治疗 PCa 的策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.