Journal
JOURNAL OF CELL SCIENCE
Volume 123, Issue 8, Pages 1295-1305Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.061002
Keywords
p53; E-cadherin; Epithelial-to-mesenchymal transition; Invasion; Metastasis
Categories
Funding
- CNRS
- Fondation de France
- Association pour la Recherche contre le Cancer [ARC 4028]
- la Ligue contre le Cancer de L'Herault
- Ministere de l'Education Nationale et de la Recherche
- ARC and Societe du Cancer
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Mutations in the p53 tumour suppressor gene are associated clinically with tumour progression and metastasis. Downregulation of the E-cadherin cell-cell adhesion molecule is a key event for epithelial to mesenchymal transition (EMT) in tumour progression. Here, we show that wild-type p53 induced to adopt a mutant conformation, and hot-spot p53 mutants, which are both transcriptionally inactive, downregulate E-cadherin expression in the colon carcinoma cell line HCT116. Downregulation of E-cadherin occurred concomitantly with the upregulation of Slug and Zeb-1, transcriptional factors known to repress E-cadherin gene expression. In addition, knockdown of Slug and Zeb-1 expression diminished p53-mediated E-cadherin repression. Knocking down endogenous mutant p53 in MDA-MB-231 and SW620 cancer cell lines lacking E-cadherin protein restored the expression of E-cadherin. Complete loss of E-cadherin expression in HCT116 cells induced morphological alterations along with upregulation of vimentin, a mesenchymal marker. These changes characteristic of the EMT phenotype were, however, not sufficient to confer invasiveness in a three-dimensional matrix. Downregulation of E-cadherin by mutant p53 was not required to promote the invasive phenotype induced by inactivation of p53. These findings indicate that independent control of E-cadherin expression and cell motility could be essential molecular events in p53 mutant-induced invasive phenotypes.
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