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

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journal contribution
posted on 06.01.2016, 10:14 by I. Celardo, F. Grespi, A. Antonov, F. Bernassola, A. V. Garabadgiu, G. Melino, I. Amelio
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.

Funding

This work has been supported by the Medical Research Council, UK and funding from RFBS (10-04-01234), MCB RAS, Russian Federal grants 11.G34.31.0069 (to GM).

History

Citation

Cell Death and Disease (2013) 4, e645

Version

VoR (Version of Record)

Published in

Cell Death and Disease (2013) 4

Publisher

Nature Publishing Group for Associazione Differenziamento e Morte Cellulare

issn

2041-4889

eissn

2041-4889

Acceptance date

22/04/2013

Available date

06/01/2016

Publisher version

http://www.nature.com/cddis/journal/v4/n5/full/cddis2013175a.html

Language

en