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

Celardo I, Grespi F, Antonov A, Bernassola F, Garabadgiu AV, Melino G, Amelio I - Cell Death Dis (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.

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.

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Related in: MedlinePlus

Positive p63/caspase-1 correlation represents a prognostic factor for good patient survival. (a–c) Three different human breast cancer data sets have been analyzed: GSE3494 (a), GSE11121 (b), GSE2034 (c). Left and central panels represent p63 and caspase-1 expression profiles in the cohorts 1 (positive correlation) and cohorts 2 (negative or absent correlation). Right panels represent patient survival estimation of p63/caspase-1-positive correlation groups compared with negative or absent correlation groups
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fig4: Positive p63/caspase-1 correlation represents a prognostic factor for good patient survival. (a–c) Three different human breast cancer data sets have been analyzed: GSE3494 (a), GSE11121 (b), GSE2034 (c). Left and central panels represent p63 and caspase-1 expression profiles in the cohorts 1 (positive correlation) and cohorts 2 (negative or absent correlation). Right panels represent patient survival estimation of p63/caspase-1-positive correlation groups compared with negative or absent correlation groups

Mentions: To further investigate clinical relevance of p63-dependent caspase-1 regulation, we evaluated the biological consequence of p63/caspase-1 axis disruption in human cancers. We used three publicly available breast cancer gene expression data sets annotated with patient survival data. In contrast to the standard approach, where patients are grouped based on high/low expression of a gene (or a gene signature which is a weighted sum of expression of several genes), we implemented a statistical procedure, which splits patients into two cohorts based on a different principle. Namely, in the first cohort we selected patients so as to maximize positive correlation between p63 and caspase-1, while all the other patients formed the second cohort (Figures 4a–c left and central panels). Thus, we clustered the samples into two biological groups: one where the p63/caspase-1 axis was present, and the second in which it was absent. To identify statistical differences in survival outcome between the two groups of patients, the R statistical package was used to perform statistical tests and to derive the P-value (for full details of the procedure see method section). Each data set showed that the cohort of patients with a strong positive correlation between p63 and caspase-1 showed improved survival outcome compared with the cohort where the p63/caspase-1 axis was disrupted (Figure 4c right panels). Notably, each of the considered data sets with low/high expression of either p63 or caspase-1 alone did not correlate with survival (data not shown). Overall, these results suggest that the presence/absence of p63/caspase-1 interactions could serve as a promising cancer biomarker of patient survival. In conclusion, our findings further elucidate p63 tumor suppressor function and also provide additional knowledge for identification of novel cancer biomarkers.


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

Celardo I, Grespi F, Antonov A, Bernassola F, Garabadgiu AV, Melino G, Amelio I - Cell Death Dis (2013)

Positive p63/caspase-1 correlation represents a prognostic factor for good patient survival. (a–c) Three different human breast cancer data sets have been analyzed: GSE3494 (a), GSE11121 (b), GSE2034 (c). Left and central panels represent p63 and caspase-1 expression profiles in the cohorts 1 (positive correlation) and cohorts 2 (negative or absent correlation). Right panels represent patient survival estimation of p63/caspase-1-positive correlation groups compared with negative or absent correlation groups
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674380&req=5

fig4: Positive p63/caspase-1 correlation represents a prognostic factor for good patient survival. (a–c) Three different human breast cancer data sets have been analyzed: GSE3494 (a), GSE11121 (b), GSE2034 (c). Left and central panels represent p63 and caspase-1 expression profiles in the cohorts 1 (positive correlation) and cohorts 2 (negative or absent correlation). Right panels represent patient survival estimation of p63/caspase-1-positive correlation groups compared with negative or absent correlation groups
Mentions: To further investigate clinical relevance of p63-dependent caspase-1 regulation, we evaluated the biological consequence of p63/caspase-1 axis disruption in human cancers. We used three publicly available breast cancer gene expression data sets annotated with patient survival data. In contrast to the standard approach, where patients are grouped based on high/low expression of a gene (or a gene signature which is a weighted sum of expression of several genes), we implemented a statistical procedure, which splits patients into two cohorts based on a different principle. Namely, in the first cohort we selected patients so as to maximize positive correlation between p63 and caspase-1, while all the other patients formed the second cohort (Figures 4a–c left and central panels). Thus, we clustered the samples into two biological groups: one where the p63/caspase-1 axis was present, and the second in which it was absent. To identify statistical differences in survival outcome between the two groups of patients, the R statistical package was used to perform statistical tests and to derive the P-value (for full details of the procedure see method section). Each data set showed that the cohort of patients with a strong positive correlation between p63 and caspase-1 showed improved survival outcome compared with the cohort where the p63/caspase-1 axis was disrupted (Figure 4c right panels). Notably, each of the considered data sets with low/high expression of either p63 or caspase-1 alone did not correlate with survival (data not shown). Overall, these results suggest that the presence/absence of p63/caspase-1 interactions could serve as a promising cancer biomarker of patient survival. In conclusion, our findings further elucidate p63 tumor suppressor function and also provide additional knowledge for identification of novel cancer biomarkers.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.

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.

Show MeSH
Related in: MedlinePlus