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

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

doi:10.1016/j.celrep.2024.114431

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

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

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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/C^Cdh1 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.

Original language	English
Article number	114431
Journal	Cell Reports
Volume	43
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2024.114431
State	Published - Jul 23 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Funding

This work was supported by NIH R01 CA196634 (X.L.), NIH NIGMS P20GM121327 (K.-W.F.), and NIH NCI R03CA256230 (K.-W.F.). This research was also aided by #IRG 22-152-34 (Y. Zhang) from the American Cancer Society. The study was supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatic Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We appreciated Dr. Kendall Simpson's efforts on proofreading (Eastern Kentucky University, Richmond, KY). Yanquan Zhang designed and performed experiments, analyzed the data, and wrote the manuscript. X.L. designed the research and supervised the project. K.-W.F. performed ChIP sequencing. D.N. and D.B.A. evaluated and scored the IHC staining. Jinpeng Liu, D.H. and C.W. performed bioinformatics analysis. J.C. and H.Z. performed the MS assay and analyzed the data. F.M. R.W. Yeqing Zhang, Y.K. C.L. Jinghui Liu, G.L. and Z.L. provided methods. The authors declare no competing interests. This work was supported by NIH R01 CA196634 (X.L.), NIH NIGMS P20GM121327 (K.-W.F.), and NIH NCI R03 R03CA256230 (K.-W.F.). This research was also aided by # IRG 22-152-34 (Y. Zhang) from the American Cancer Society . The study was supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatic Shared Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ). We appreciated Dr. Kendall Simpson\u2019s efforts on proofreading (Eastern Kentucky University, Richmond, KY).

Funders	Funder number
Eastern Kentucky, University
American Cancer Society-Michigan Cancer Research Fund
NCI/NIH	R03 R03CA256230, IRG 22-152-34, 22-152-34, R03CA256230
NIH/NIGMS	P20GM121327
University of Kentucky Markey Cancer Center	P30CA177558
University of Kentucky Markey Cancer Center
NIH	R01 CA196634

Keywords

APC/C
BET inhibitor resistance
BRD4
CP: Cancer
CP: Molecular biology
PLK1
phosphorylation
prostate cancer

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2024.114431

Cite this

Zhang, Y., Fong, K. W., Mao, F., Wang, R., Allison, D. B., Napier, D., He, D., Liu, J., Zhang, Y., Chen, J., Kong, Y., Li, C., Li, G., Liu, J., Li, Z., Zhu, H., Wang, C., & Liu, X. (2024). Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis. Cell Reports, 43(7), Article 114431. https://doi.org/10.1016/j.celrep.2024.114431

@article{b25491e6653f467c95f4d11c1d303d5e,

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

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, BET inhibitor resistance, BRD4, CP: Cancer, CP: Molecular biology, PLK1, phosphorylation, prostate cancer",

author = "Yanquan Zhang and Fong, \{Ka Wing\} and Fengyi Mao and Ruixin Wang and Allison, \{Derek B.\} and Dana Napier and Daheng He and Jinpeng Liu and Yeqing Zhang and Jing Chen and Yifan Kong and Chaohao Li and Guangbing Li and Jinghui Liu and Zhiguo Li and Haining Zhu and Chi Wang and Xiaoqi Liu",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jul,

day = "23",

doi = "10.1016/j.celrep.2024.114431",

language = "English",

volume = "43",

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Zhang, Y , Fong, KW, Mao, F, Wang, R, Allison, DB, Napier, D, He, D, Liu, J, Zhang, Y, Chen, J, Kong, Y, Li, C, Li, G, Liu, J , Li, Z, Zhu, H, Wang, C & Liu, X 2024, 'Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis', Cell Reports, vol. 43, no. 7, 114431. https://doi.org/10.1016/j.celrep.2024.114431

TY - JOUR

T1 - Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis

AU - Zhang, Yanquan

AU - Fong, Ka Wing

AU - Mao, Fengyi

AU - Wang, Ruixin

AU - Allison, Derek B.

AU - Napier, Dana

AU - He, Daheng

AU - Liu, Jinpeng

AU - Zhang, Yeqing

AU - Chen, Jing

AU - Kong, Yifan

AU - Li, Chaohao

AU - Li, Guangbing

AU - Liu, Jinghui

AU - Li, Zhiguo

AU - Zhu, Haining

AU - Wang, Chi

AU - Liu, Xiaoqi

PY - 2024/7/23

Y1 - 2024/7/23

N2 - 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.

AB - 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.

KW - APC/C

KW - BET inhibitor resistance

KW - BRD4

KW - CP: Cancer

KW - CP: Molecular biology

KW - PLK1

KW - phosphorylation

KW - prostate cancer

UR - https://www.scopus.com/pages/publications/85197272549

UR - https://www.scopus.com/inward/citedby.url?scp=85197272549&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2024.114431

DO - 10.1016/j.celrep.2024.114431

M3 - Article

C2 - 38968071

AN - SCOPUS:85197272549

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 114431

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Cite this