Opposing Roles of Wild-type and Mutant p53 in the Process of Epithelial to Mesenchymal Transition

Abstract

The central role of an aberrantly activated EMT program in defining the critical features of aggressive carcinomas is well documented and includes cell plasticity, metastatic dissemination, drug resistance, and cancer stem cell-like phenotypes. The p53 tumor suppressor is critical for leashing off all the features mentioned above. On the molecular level, the suppression of these effects is exerted by p53 via regulation of its target genes, whose products are involved in cell cycle, apoptosis, autophagy, DNA repair, and interactions with immune cells. Importantly, a set of specific mutations in the TP53 gene (named Gain-of-Function mutations) converts this tumor suppressor into an oncogene. In this review, we attempted to contrast different regulatory roles of wild-type and mutant p53 in the multi-faceted process of EMT.

Keywords: EMT; epigenetic regulation; epithelial to mesenchymal transition; microRNA; mutant p53; p53; wild-type p53.

FIGURE 1

p53 regulates EMT factors through micro-RNA. The p53 protein directly regulates the expression of miR-200 and miR-34 micro-RNA families decreasing Zeb and Snail expression respectively. Mutations in TP53 gene disrupt this link and promote EMT.

FIGURE 2

The crosstalk between p53, Mdm2 and EMT transcription factors. The wild-type p53 forms the complex with Mdm2 and EMT-TFs mediating their polyubiquitination and proteasomal degradation. TP53 mutations abolish the ability of p53 to associate with EMT-TFs and to form the complex with Mdm2 that results in EMT-TFs stabilization and promotion of EMT process.

FIGURE 3

p53 affects various signalling pathways involved in the regulation of EMT. p53 directly activates the transcription of CDH1 (E-cadherin coding gene) by binding to its enhancer promoting epithelial phenotype. Additionally, p53 activates the expression of E-cadherin at the epigenetic level through recruiting JMJD3/KDM6B demethylase that removes repressive marks from histones and promotes the activation of p53 target genes. Furthermore, p53 negatively regulates EZH2 (Enhancer of Zeste Homolog 2) that represses E-cadherin. p53-mediated expression of BMI1 contributes to the maintenance of a repressive mark in the TWIST1 promoter region. Mutations in p53 lead to suppression of BMI1 and positive regulation of TWIST1. In addition, mutant p53 activates EMT via the TGF-β signalling cascade. In turn, Slug and Vimentin inhibit the p53 effects, e.g., suppressing PUMA-dependent apoptosis in response to DNA damage. Chk2 kinase is able to block the effect of Vimentin and support the p53 effects. PI3K/Akt/mTOR signalling axis negatively regulates p53, thereby contributing to EMT in p53wt cells.