Caspase-1 is a novel target of p63 in tumor suppression

Celardo, I; Grespi, F; Antonov, A; Bernassola, F; Garabadgiu, A V; Melino, G; Amelio, I

Abstract

p63 is a p53 family transcription factor, which besides unique roles in epithelial development, shares tumor suppressive activity with its homolog p53. The p63 gene has different transcriptional start sites, which generate two N-terminal isoforms (transactivation domain (TA)p63 and amino terminal truncated protein(ΔN)p63); in addition alternative splicing at the 5′-end give rise to at least five C-terminal isoforms. This complexity of gene structure has probably fostered the debate and controversy on p63 function in cancer, with TP63-harboring two distinctive promoters, codifying for the TAp63 and ΔNp63 isoforms, and having discrete functions. However, ΔNp63 also drives expression of target genes that have a relevant role in cancer and metastasis. In this study, we identified a novel p63 transcriptional target, caspase-1. Caspase-1 is proinflammatory caspase, which functions in tumor suppression. We show that both p63 isoforms promote caspase-1 expression by physical binding to its promoter. Consistent with our in vitro findings, we also identified a direct correlation between p63 and caspase-1 expression in human cancer data sets. In addition, survival estimation analysis demonstrated that functional interaction between p63 and caspase-1 represents a predictor of positive survival outcome in human cancers. Overall, our data report a novel p63 target gene involved in tumor suppression, and the clinical analysis underlines the biological relevance of this finding and suggests a further clinically predictive biomarker.

Citation

Celardo, I., Grespi, F., Antonov, A., Bernassola, F., Garabadgiu, A. V., Melino, G., & Amelio, I. (2013). Caspase-1 is a novel target of p63 in tumor suppression. Cell Death and Disease, 4(5), Article e645. https://doi.org/10.1038/cddis.2013.175

• Journal Article Type: Article
• Acceptance Date: Apr 22, 2013
• Online Publication Date: May 23, 2013
• Publication Date: 2013-05
• Deposit Date: Apr 1, 2020
• Journal: Cell Death & Disease
• Print ISSN: 2041-4889
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 5
• Article Number: e645
• DOI: https://doi.org/10.1038/cddis.2013.175
• Keywords: Immunology; Cell Biology; Cancer Research; Cellular and Molecular Neuroscience
• Public URL: https://nottingham-repository.worktribe.com/output/4237288
• Publisher URL: https://www.nature.com/articles/cddis2013175