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

Authors

• Yanquan Zhang, University of KentuckyFollow
• Ka-Wing Fong, University of Kentucky
• Fengyi Mao, University of Kentucky
• Ruixin Wang, University of Kentucky
• Derek B. Allison, University of Kentucky
• Dana Napier, University of Kentucky
• Daheng He, University of Kentucky
• Jinpeng Liu, University of Kentucky
• Yeqing Zhang, University of Kentucky
• Jing Chen, University of Kentucky
• Yifan Kong, University of Kentucky
• Chaohao Li, University of Kentucky
• Guangbing Li, University of Kentucky
• Jinghui Liu, University of Kentucky
• Zhiguo Li, University of Kentucky
• Haining Zhu, University of Kentucky
• Chi Wang, University of Kentucky
• Xiaoqi Liu, University of KentuckyFollow

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

Notes/Citation Information

© 2024 The Author(s). Published by Elsevier Inc.

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