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Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis.
- Source :
-
Cell reports [Cell Rep] 2024 Jul 23; Vol. 43 (7), pp. 114431. Date of Electronic Publication: 2024 Jul 04. - Publication Year :
- 2024
-
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 <superscript>Cdh1</superscript> 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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Male
Phosphorylation
Cell Line, Tumor
Proteolysis drug effects
Nuclear Proteins metabolism
Animals
CDC2 Protein Kinase metabolism
Mice, Nude
Mice
Proteasome Endopeptidase Complex metabolism
Bromodomain Containing Proteins
Repressor Proteins
Polo-Like Kinase 1
Cell Cycle Proteins metabolism
Prostatic Neoplasms metabolism
Prostatic Neoplasms pathology
Prostatic Neoplasms drug therapy
Prostatic Neoplasms genetics
Proto-Oncogene Proteins metabolism
Mitosis drug effects
Protein Serine-Threonine Kinases metabolism
Transcription Factors metabolism
Drug Resistance, Neoplasm drug effects
Azepines pharmacology
Triazoles pharmacology
Docetaxel pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 38968071
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114431