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-tar- geted 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. Intrigu-ingly, 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.
Document Type
Article
Publication Date
7-23-2024
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.celrep.2024.114431
Repository Citation
Zhang, Yanquan; Fong, Ka-Wing; Mao, Fengyi; Wang, Ruixin; Allison, Derek B.; Napier, Dana; He, Daheng; Liu, Jinpeng; Zhang, Yeqing; Chen, Jing; Kong, Yifan; Li, Chaohao; Li, Guangbing; Liu, Jinghui; Li, Zhiguo; Zhu, Haining; Wang, Chi; and Liu, Xiaoqi, "Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis" (2024). Markey Cancer Center Faculty Publications. 214.
https://uknowledge.uky.edu/markey_facpub/214
Notes/Citation Information
© 2024 The Author(s). Published by Elsevier Inc.