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The non-apoptotic function of Caspase-8 in negatively regulating the CDK9 mediated Ser2 phosphorylation of RNA Polymerase II in cervical cancer

ABSTRACT: Analysis of the gene expression profile of the cervical cancer cell line HeLa in the presence or absence of Caspase-8 expression. The result offered an useful insight into the altered gene expression of metastasis associated genes due to the negative regulation of RNAPII mediated gene transcription by Caspase-8

ORGANISM(S): Homo sapiens

PROVIDER: GSE217360 | GEO | 2022/11/23

REPOSITORIES: GEO

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The non-apoptotic function of Caspase-8 in negatively regulating the CDK9 mediated Ser2 phosphorylation of RNA Polymerase II in cervical cancer

Project description:Cervical cancer is the fourth most frequently diagnosed and fatal gynecological cancer. 15-61% of all cases metastasize and develop chemoresistance, reducing the 5-year survival of cervical cancer patients to as low as 17%. Therefore, unraveling the mechanisms contributing to metastasis is critical in developing better-targeted therapies against it. Here, we have identified a novel mechanism where nuclear Caspase-8 directly interacts with and inhibits the activity of CDK9, thereby modulating RNAPII-mediated global transcription, including those of cell-migration and -invasion-associated genes. Crucially, low Caspase-8 expression in cervical cancer patients leads to poor prognosis, higher CDK9 phosphorylation at Thr186, and increased RNAPII activity in cervical cancer cell lines and patient biopsies. Caspase-NT8 knock-out cells were also more resistant to the small-molecule CDK9 inhibitor BAY1251152 in both 2D- and 3D-culture conditions. Combining BAY1251152 with Cisplatin synergistically overcame chemoresistance of Caspase-8 deficient cervical cancer cells. Therefore, Caspase-8 expression could be a marker in chemoresistant cervical tumors, suggesting CDK9 inhibitor treatment for their sensitization to Cisplatin-based chemotherapy.

2023-03-11 | PXD038102 | Pride

The non-apoptotic function of Caspase-8 in negatively regulating the CDK9-mediated Ser2 phosphorylation of RNA polymerase II in cervical cancer.

Project description:Cervical cancer is the fourth most frequently diagnosed and fatal gynecological cancer. 15-61% of all cases metastasize and develop chemoresistance, reducing the 5-year survival of cervical cancer patients to as low as 17%. Therefore, unraveling the mechanisms contributing to metastasis is critical in developing better-targeted therapies against it. Here, we have identified a novel mechanism where nuclear Caspase-8 directly interacts with and inhibits the activity of CDK9, thereby modulating RNAPII-mediated global transcription, including those of cell-migration- and cell-invasion-associated genes. Crucially, low Caspase-8 expression in cervical cancer patients leads to poor prognosis, higher CDK9 phosphorylation at Thr186, and increased RNAPII activity in cervical cancer cell lines and patient biopsies. Caspase-8 knock-out cells were also more resistant to the small-molecule CDK9 inhibitor BAY1251152 in both 2D- and 3D-culture conditions. Combining BAY1251152 with Cisplatin synergistically overcame chemoresistance of Caspase-8-deficient cervical cancer cells. Therefore, Caspase-8 expression could be a marker in chemoresistant cervical tumors, suggesting CDK9 inhibitor treatment for their sensitization to Cisplatin-based chemotherapy.

| S-EPMC9674771 | biostudies-literature

The non-apoptotic function of Caspase-8 in negatively regulating the CDK9 mediated Ser2 phosphorylation of RNA Polymerase II in cervical cancer

Project description:The non-apoptotic function of Caspase-8 in negatively regulating the CDK9 mediated Ser2 phosphorylation of RNA Polymerase II in cervical cancer

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Aurora kinase B-dependent phosphorylation regulates caspase-2 activity and function

Project description:Mitotic catastrophe (MC) is an important mechanism to remove cells that become polyploid or aneuploid, as an oncosuppressive mechanism. Previous studies have demonstrated that the activation and catalytic function of caspase-2 is a key step in MC, to trigger apoptosis and/or cell cycle arrest of such defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here we show that Aurora kinase B (AURKB), a key mitotic kinase, phosphorylates caspase-2 at a highly conserved residue S384 and inhibits its catalytic activity and function. We identified six new phosphorylation sites in caspase-2 and further demonstrated that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.

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2023-08-21 | GSE241017 | GEO

Caspase-10 is a negative regulator of caspase-8-mediated cell death with gene inductive properties

Project description:Formation of the Death-Inducing Signalling Complex (DISC) initiates the extrinsic apoptotic signalling cascade. Caspase-8 and its regulator cFLIP control death signalling by binding to the receptor via DISC-bound FADD. By elucidating the function of Caspase-10, a close homologue of caspase-8, we unexpectedly found that caspase-10 negatively regulates caspase-8-mediated cell death signalling in the DISC. We demonstrate that caspase-10 inhibits the activation of caspase-8 independent of cFLIP. Furthermore, we show that caspase-8 does not compete with other tandem DED proteins such as cFLIP or caspase-10 in binding via FADD to the receptor as current models suggest. By utilizing caspase-8 knockout cells, we demonstrate that caspase-8 has to be placed upstream of both cFLIP and caspase-10 in the DISC. We further show that DISC formation and/or stability depends on caspase-8 but is independent from its enzymatic activity. Surprisingly, we identified caspase-10 to rewire DISC-signalling to NF-kB activation and cell survival. Our data are consistent with a model in which caspase-10 and cFLIP co-ordinately regulate caspase-8-mediated cell death signalling.

2016-04-20 | GSE75365 | GEO

Cervical microbiota

Project description:Cervical microbiota

| PRJEB55377 | ENA

Cervical cancer

Project description:Cervical cancer

| PRJNA144107 | ENA

RNA-sequencing analysis of the KYSE150 cells overexpressing caspase-8 mutants (M4, M6, M10, M13) or wild-type caspase-8

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are using RNA sequencing analysis to test the effects of overexpressing caspase-8 mutants or wild-type caspase-8 on the mRNA of KYSE150 cells. Methods: KYSE150 cells were transfected with caspase-8 mutants or wild-type caspase-8 for 48 hours in 1640 medium plus 10% serum. Two independent replicates were plated, transfected in parallel for each caspase-8 mutants or wild-type caspase-8. Results: Log-fold changes of mRNAs between caspase-8 mutants and wild-type caspase-8 group were selected with a significance threshod of p<0.05. There are 3974 overlapping differentially expressed genes in the caspase-8 mutant cells compared to the wild-type caspase-8 cells. Conclusions: Our study determined the mRNA changes of caspase-8 mutant KYSE150 cells compared to the wild-type caspase-8 cells.

2022-03-17 | GSE198569 | GEO

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