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Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation.

ABSTRACT: The PIDDosome is a multiprotein complex that drives activation of caspase-2, an endopeptidase originally implicated in apoptosis. Yet, unlike other caspases involved in cell death and inflammation, caspase-2 seems to exert additional versatile functions unrelated to cell death. These emerging roles range from control of transcription factor activity to ploidy surveillance. Thus, caspase-2 and the PIDDosome act as a critical regulatory unit controlling cellular differentiation processes during organogenesis and regeneration. These newly established functions of the PIDDosome and its downstream effector render its components attractive targets for drug-development aiming to prevent fatty liver diseases, neurodegenerative disorders or osteoporosis.

SUBMITTER: Sladky VC

PROVIDER: S-EPMC7308375 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation.

Sladky Valentina C VC Villunger Andreas A

Cell death and differentiation 20200515 7

The PIDDosome is a multiprotein complex that drives activation of caspase-2, an endopeptidase originally implicated in apoptosis. Yet, unlike other caspases involved in cell death and inflammation, caspase-2 seems to exert additional versatile functions unrelated to cell death. These emerging roles range from control of transcription factor activity to ploidy surveillance. Thus, caspase-2 and the PIDDosome act as a critical regulatory unit controlling cellular differentiation processes during or ...[more]

PMID: 32415279

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Project description:BackgroundStem cell characteristics are an important feature of human cancer cells and play a major role in the therapy resistance of tumours. Strategies to target cancer stem cells are thus of major importance for cancer therapy. Differentiation therapy by nucleoside drugs represents an attractive approach for the elimination of cancer stem cells. However, even if it is generally assumed that the activity of these drugs is mediated by their ability to modulate epigenetic pathways, their precise mode of action remains to be established. We therefore analysed the potential of three nucleoside analogues to induce differentiation of the embryonic cancer stem cell line NTERA 2 D1 and compared their effect to the natural ligand retinoic acid.Methodology/principal findingsAll nucleoside analogues analyzed, but not retinoic acid, triggered proteolytic degradation of the Polycomb group protein EZH2. Two of them, 3-Deazaneplanocin A (DZNep) and 2'-deoxy-5-azacytidine (decitabine), also induced a decrease in global DNA methylation. Nevertheless, only decitabine and 1beta-arabinofuranosylcytosine (cytarabine) effectively triggered neuronal differentiation of NT2 cells. We show that drug-induced differentiation, in contrast to retinoic acid induction, is caused by caspase activation, which mediates depletion of the stem cell factors NANOG and OCT4. Consistent with this observation, protein degradation and differentiation could be counteracted by co-treatment with caspase inhibitors or by depletion of CASPASE-3 and CASPASE-7 through dsRNA interference. In agreement with this, OCT4 was found to be a direct in-vitro-target of CASPASE-7.Conclusions/significanceWe show that drug-induced differentiation is not a consequence of pharmacologic epigenetic modulation, but is induced by the degradation of stem-cell-specific proteins by caspases. Our results thus uncover a novel pathway that induces differentiation of embryonic cancer stem cells and is triggered by the established anticancer drugs cytarabine and decitabine. These findings suggest new approaches for directly targeting the stem cell fraction of human tumours.

Dataset Information

Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation.

Publications

Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation.

Similar Datasets

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