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

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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267369 | 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

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.

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

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

Ubiquitylation-dependent localization of PLK1 in mitosis.

Project description:Polo-like kinase 1 (PLK1) critically regulates mitosis through its dynamic localization to kinetochores, centrosomes and the midzone. The polo-box domain (PBD) and activity of PLK1 mediate its recruitment to mitotic structures, but the mechanisms regulating PLK1 dynamics remain poorly understood. Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors. Expression of a non-ubiquitylatable PLK1-K492R mutant phenocopies inactivation of CUL3-KLHL22. KLHL22 associates with the mitotic spindle and its interaction with PLK1 increases on chromosome bi-orientation. Our data suggest that CUL3-KLHL22-mediated ubiquitylation signals degradation-independent removal of PLK1 from kinetochores and SAC satisfaction, which are required for faithful mitosis.

| S-EPMC7116173 | biostudies-literature

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

Project description:Capture-C of G1E ER4 cell line in a nocodazole arrest-release experiment anchored at multiple gene promoters to quantify long-range chromatin interactions at the mitosis-G1 transition.

2016-06-15 | GSE83290 | GEO

cdr2 siRNA knockdown during passage through mitosis: HeLa cells, Rat1 wild type and c-myc null cells

Project description:[Hela cells]: We performed cdr2 knockdown with a pool of 4 cdr2-specific siRNAs to test whether cdr2 may regulate c-myc target genes as cells passage through mitosis. [Rat1a wild type and myc null cells]: We performed cdr2 knockdown using a pool of 4 cdr2-specific siRNAs to test whether cdr2 may regulate c-myc target genes as cells passage through mitosis. [HeLa cells]: Cells were transfected with control or cdr2 siRNAs and then cells were synchronized in mitosis using a sequential thymidine/nocodazole block. Cells were subsequently released from nocodazole block and after 3 hours RNA was harvested for microarray analysis [Rat-1 wild type (TGR) and c-myc null (15.19) cells]: Cells were transfected with control or cdr2 siRNAs and then cells were synchronized in mitosis using a sequential thymidine/nocodazole block. Cells were then subsequently released from nocodazole block and after 3 hours RNA was harvested for microarray analysis

2010-04-07 | E-GEOD-20037 | biostudies-arrayexpress

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