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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267290 | GEO | 2024/06/01

REPOSITORIES: GEO

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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

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

| PRJNA1111004 | ENA

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

A hyperactive transcriptional state marks genome reactivation at the mitosis-G1 transition [Hist]

Project description:ChIP-seq of H3K27Ac in the G1E-ER4 cell line in prometaphase (nocodazole block), between anaphase-telophase (nocodazole release 40min), and interphase (asynchronous).

2016-06-15 | GSE83255 | GEO

A hyperactive transcriptional state marks genome reactivation at the mitosis-G1 transition [Hist]

Project description:ChIP-seq of H3K27Ac in the G1E-ER4 cell line in prometaphase (nocodazole block), between anaphase-telophase (nocodazole release 40min), and interphase (asynchronous). Nocodazole arrest-release in G1E ER4 cell line under conditions of 13h estradiol treatment.

2016-06-15 | E-GEOD-83255 | biostudies-arrayexpress

Oncogenic BRD4-NUT protein interactions

Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 among a small number of candidates associated with BRD4-NUT in NMC patient cells but not present in 293T cells.

2017-04-05 | PXD005786 | Pride

Chromatin occupancy assessment an AML cell line treated with vehicle control, BETi, MDM2i, or a drug combination (BRD4-bound profiles)

Project description:BRD4 chromatin occupancy changes in human OCI-AML3 cells treated with DMSO (vehicle control), the BET inhibitor CPI-203, the MDM2 inhibitor Nutlin-3a, or a combination of both drugs, were compared. Method: Genomic DNA from the OCI-AML3 cell line treated for 24 hrs with either DMSO, CPI-203, Nutlin-3a or a combination of both drugs was extracted, BRD4-bound chromatin was immunoprecipitated, then DNA was sequenced with an Illumina NextSeq 500 sequencer. Sequence reads passing the quality control filters were aligned using Bowtie2 and then analysed with SICER.

2020-11-04 | GSE132247 | GEO

BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536.

Project description:A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a K i = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.

| S-EPMC4499818 | biostudies-literature

Molecular dynamics of PLK1 during mitosis.

Project description:Polo-like kinase 1 (PLK1) is a key regulator of eukaryotic cell division. During mitosis, dynamic regulation of PLK1 is crucial for its roles in centrosome maturation, spindle assembly, microtubule-kinetochore attachment, and cytokinesis. Similar to other members of the PLK family, the molecular architecture of PLK1 protein is characterized by 2 domains-the kinase domain and the regulatory substrate-binding domain (polo-box domain)-that cooperate and control PLK1 function during mitosis. Mitotic cells employ many layers of regulation to activate and target PLK1 to different cellular structures in a timely manner. During the last decade, numerous studies have shed light on the precise molecular mechanisms orchestrating the mitotic activity of PLK1 in time and space. This review aims to discuss available data and concepts related to regulation of the molecular dynamics of human PLK1 during mitotic progression.

| S-EPMC4905186 | biostudies-other

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