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Elevating PLK1 Overcomes BETi-Resistance in Prostate Cancer via Triggering BRD4 Phosphorylation-dependent Degradation in Mitosis

ABSTRACT: Elevating PLK1 Overcomes BETi-Resistance in Prostate Cancer via Triggering BRD4 Phosphorylation-dependent Degradation in Mitosis

PROVIDER: PRJNA1111004 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29006656_1.fastq.gz	Fastqsanger.gz
	SRR29006656_2.fastq.gz	Fastqsanger.gz
	SRR29006657_1.fastq.gz	Fastqsanger.gz
	SRR29006657_2.fastq.gz	Fastqsanger.gz
	SRR29006658_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Elevating PLK1 Overcomes BETi-Resistance in Prostate Cancer via Triggering BRD4 Phosphorylation-dependent Degradation in Mitosis [ChIP-seq]

Project description:Elevating PLK1 Overcomes BETi-Resistance in Prostate Cancer via Triggering BRD4 Phosphorylation-dependent Degradation in Mitosis [ChIP-seq]

| PRJNA1111351 | ENA

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

Project description: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.

| S-EPMC11334074 | biostudies-literature

Elevating PLK1 Overcomes BETi-Resistance in Prostate Cancer via Triggering BRD4 Phosphorylation-dependent Degradation in Mitosis

Project description:To investigate the effect of phosphorylated BRD4 at S24 and S1100 on transcription, we established C4-2 stable expressing BRD4 WT, S24/1100A, S24/1100D cell lines in which endogenous BRD4 has been knocked down by shRNA targeted to 3'-UTR. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at 18 hour treatment of nocodazole.

2024-06-01 | GSE267290 | GEO

Elevating PLK1 Overcomes BETi-Resistance in Prostate Cancer via Triggering BRD4 Phosphorylation-dependent Degradation in Mitosis [ChIP-seq]

Project description:To investigate the effect of phosphorylated BRD4 at S24 and S1100 on transcription, we established C4-2 stable expressing BRD4 WT, S24/1100A, S24/1100D cell lines in which endogenous BRD4 has been knocked down by shRNA targeted to 3'-UTR. We then performed a CUT&RUN assay using anti-BRD4 or anti-H3K27Ac antibodies followed with a sequencing of ChIPed DNA from 4 different cells at 18 hour treatment of nocodazole.

2024-06-01 | GSE267369 | GEO

Dynamic phosphorylation of G9a by Plk1 and PP2A modulates its catalytic activity and chromosome accessibility during mitosis

Project description:Phosphorylation of Ser10 of histone H3 (H3S10p), together with the adjacent dimethylation of Lys9 (H3K9me2), has been proposed to function as a ‘phospho-methyl switch’ to regulate mitotic chromosome dynamics and control peripheral heterochromatin localization (1, 2). Despite of immensely understanding the regulation of H3S10 phosphorylation, how this modification temporarily masks the H3K9me2 mark during mitosis is poorly understood. Herein, we report that the master mitotic kinase Plk1 phosphorylates G9a at Thr1045 (pT1045) in vitro and in vivo at early mitosis. T1045p inhibits G9a catalytic activity, leading to decrease H3K9me2 levels. RNA-sequencing analysis showed that the phospho-mimic T1045 mutant of G9a (T1045E) compromised its repressive activity on several targeted genes, which was confirmed by luciferase reporter assays. Using genome-wide epigenomic technologies, we found that T1045E mutant displayed reduced H3K9me2 level, accompanied with increased chromatin accessibility, compared to the wild-type G9a cells. Finally, we found that T1045 phosphorylation could be removed by the phosphatase PP2A at late mitosis, which inversely reactivated G9a activity on H3K9me2 level, correlated with lower levels of H3S10p. Therefore, our result may provide a mechanistic explanation for ‘phospho-methyl switch’ and highlight the importance of Plk1 and PP2A-mediated dynamic regulation of G9a during mitosis.

2023-07-17 | GSE223359 | GEO

Bulk mitotic ATACseq for Polo-like kinase 1 maintains transcription and chromosomal accessibility during mitosis

Project description:We found that Polo-like kinase 1 (Plk1) activity directly on chromatin sustains global transcription and chromosomal accessibility in mitosis. Inhibition of Plk1 leads to significant overall downregulation of accessibility on mitotic chromosomes, especially at promoter and transcription start site (TSS) regions. Therefore, Plk1 activity sustains global chromosomal accessibility in mitosis, facilitating transcription factor binding and ensuring proper transcriptional activity, which maintains mitotic fidelity.

2025-11-18 | GSE282486 | GEO

Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations

Project description:Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have been developed and tested in clinical trials. However, these molecules alone were not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle. To date, it is unclear which of these events most crucially depend on PLK1 activity. We used a CRISPR-based genome-wide screening strategy to identify genes whose inactivation enhances cell proliferation defects upon partial chemical inhibition of PLK1. Genes identified encode proteins that are functionally linked to PLK1 in multiple ways. Among them, factors that promote centromere and kinetochore function were clearly enriched. In particular, inactivation of the kinesin KIF18A or SKA1 in PLK1-compromised cells results in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. Our results suggest that functions of PLK1 at kinetochores are most sensitive to its inhibition, and point at KIF18A as a possible target for combinatorial therapies using existing PLK1 inhibitors.

2023-10-02 | GSE228155 | GEO

Mass spectrometry analysis of in vitro PLK1 phosphorylation

Project description:Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

2024-11-01 | PXD053933 | Pride

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation: siEYA4 pY IP-MS

Project description:The Eyes Absent family of proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour promoting across a range of cancer types. To date, the molecular targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as a direct interactor and phosphatase substrate of both EYA4 and EYA1, with pY445 on PLK1 being the primary target site. EYA-mediated dephosphorylation of PLK1 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and the PLK1-activating proteins BORA and CEP192. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a novel phosphotyrosine signalling network governing PLK1 and mitosis. This work provides a mechanism of cell killing for EYA phosphatase inhibitors with important therapeutic implications.

2024-02-26 | PXD036430 | Pride

PLK1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

Project description:We found that synergy between the antiandrogen abiraterone and Plk1 inhibitors was completely independent of abiraterone's effects on AR signaling. To identify AR-independent effects of abiraterone we designed a comprehensive RNA seq experiment. This identified an AR-independent synergy-specific gene set signature that was induced by abiraterone treatment and was dominated by gene sets related to mitosis and the mitotic spindle. AR-independent effects of abiraterone were isolated by including an enzalutamide treatment arm and by utilizing cancer cell lines that do not express the AR. Synergy-specific gene expression changes were identified by using cell lines that responded synergistically or non-synergistically to combined abiraterone and onvansertib.

2023-01-24 | GSE217537 | GEO

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