The genetic profile of METTLs-KD and the inhibition of PLK1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA834036 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19032729_1.fastq.gz | Fastqsanger.gz | |||
| SRR19032729_2.fastq.gz | Fastqsanger.gz | |||
| SRR19032730_1.fastq.gz | Fastqsanger.gz | |||
| SRR19032730_2.fastq.gz | Fastqsanger.gz | |||
| SRR19032731_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations
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Project description:Transcriptional profiling of mouse aortas comparing control wild-type animals with aortas from three different Plk1(+/-) mice. Goal was to determine the effects of Plk1 haploinsufficiency in aorta expression profiles.
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Project description:Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors of the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset of AML patients. However, the clinical success of PLK1 inhibitors remains hindered by a lack of predictive biomarkers. The Fanconi anemia (FA) pathway, a tumor-suppressive network comprised of at least 22 genes, is frequently mutated in sporadic AML. Here, we demonstrate that FA pathway disruption sensitizes AML cells to PLK1 inhibition. Mechanistically, we identify novel interactions between PLK1 and both FANCA and FANCD2 at mitotic centromeres. We demonstrate that PLK1 inhibition impairs recruitment of FANCD2 to mitotic centromeres, induces damage to mitotic chromosomes, and triggers mitotic collapse in FANCA-deficient cells. Our findings indicate that PLK1 inhibition targets mitotic vulnerabilities specific to FA pathway-deficient cells and implicate FA pathway mutations as potential biomarkers for the identification of patients likely to benefit from PLK1 inhibitors.
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Project description:Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumor growth remains enigmatic. Employing an unbiased systems-based approach, we uncovered a new role of DNAJ-PKAc oncoprotein in FLC and identified downstream kinases involved in this process. Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumor growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues. Our findings underscore the role of DNAJ-PKAc in rewiring signaling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.
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Project description:PLK1 inhibitors are emerging anti-cancer agents being tested in monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models shows potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, while sensitive cells engage apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that non-selective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their anti-proliferative and pro-inflammatory effects via PLK1 inhibition. This work reveals overlooked impacts of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve response to targeted therapies.
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Project description:Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2-M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/ expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.
2022-03-08 | PXD031110 | Pride
Project description:Polo-like kinase 1 (Plk1) is an essential protein kinase that promotes faithful mitotic progression in eukaryotes. Plk1 subcellular localization and substrate interactions are tightly controlled and require binding of Plk1 to phosphorylated sequences. Here, we use quantitative proteomics to identify phosphorylation-dependent interactions within the Plk1 network in human mitotic HeLa cells using kinase inhibitors and a Plk1 mutant deficient in phosphorylation-dependent substrate binding. We find that many interactions are abolished upon kinase inhibition; however, a subset are protected from phosphatase opposition or are unopposed, resulting in persistent Plk1-substrate interactions. This subset includes Phosphoprotein Phosphatase 6 (PP6), whose activity towards Aurora kinase A (AURKA) is inhibited by Plk1. This Plk1-PP6 interaction creates a feedback loop that coordinates and reinforces the activities of Plk1 and AURKA during mitotic entry and is terminated by Plk1 degradation during mitotic exit. Collectively, this work provides a cellular mechanism for the observed regulation of AURKA by Plk1.
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