Cross-talk between mutant p53 and p62/SQSTM1 augments cancer cell migration by promoting the degradation of cell adhesion proteins

Significance

Missense mutations in the TP53 gene, encoding the p53 tumor suppressor, are very frequent in human cancer. Some of those mutations, particularly the more common (“hotspot”) ones, not only abrogate p53’s tumor suppressor activities but also endow the mutant protein with oncogenic gain of function (GOF). We report that p53 ^R273H, the most common p53 mutant in pancreatic cancer, interacts with the SQSTM1/p62 protein to accelerate the degradation of cell adhesion proteins. This enables pancreatic cancer cells to detach from the epithelial sheet and engage in individualized cell migration, probably augmenting metastatic spread. By providing insights into mechanisms that underpin mutant p53 GOF, this study may suggest ways to interfere with the progression of cancers bearing particular p53 mutants.

Abstract

Missense mutations in the p53 tumor suppressor abound in human cancer. Common (“hotspot”) mutations endow mutant p53 (mutp53) proteins with oncogenic gain of function (GOF), including enhanced cell migration and invasiveness, favoring cancer progression. GOF is usually attributed to transcriptional effects of mutp53. To elucidate transcription-independent effects of mutp53, we characterized the protein interactome of the p53 ^R273H mutant in cells derived from pancreatic ductal adenocarcinoma (PDAC), where p53 ^R273H is the most frequent p53 mutant. We now report that p53 ^R273H, but not the p53 ^R175H hotspot mutant, interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner. Mechanistically, the p53 ^R273H-p62 axis drives the proteasomal degradation of several cell junction–associated proteins, including the gap junction protein Connexin 43, facilitating scattered cell migration. Concordantly, down-regulation of Connexin 43 augments PDAC cell migration, while its forced overexpression blunts the promigratory effect of the p53 ^R273H-p62 axis. These findings define a mechanism of mutp53 GOF.