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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

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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: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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Functional interplay between caspase cleavage and phosphorylation sculpts the apoptotic proteome.

Project description:Caspase proteases are principal mediators of apoptosis, where they cleave hundreds of proteins. Phosphorylation also plays an important role in apoptosis, although the extent to which proteolytic and phosphorylation pathways crosstalk during programmed cell death remains poorly understood. Using a quantitative proteomic platform that integrates phosphorylation sites into the topographical maps of proteins, we identify a cohort of over 500 apoptosis-specific phosphorylation events and show that they are enriched on cleaved proteins and clustered around sites of caspase proteolysis. We find that caspase cleavage can expose new sites for phosphorylation, and, conversely, that phosphorylation at the +3 position of cleavage sites can directly promote substrate proteolysis by caspase-8. This study provides a global portrait of the apoptotic phosphoproteome, revealing heretofore unrecognized forms of functional crosstalk between phosphorylation and caspase proteolytic pathways that lead to enhanced rates of protein cleavage and the unveiling of new sites for phosphorylation.

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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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