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

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 p53R273H mutant in cells derived from pancreatic ductal adenocarcinoma (PDAC), where p53(R273H) is the most frequent p53 mutant. We now report that p53R273H, 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.

Automated summary

The p53R273H mutant interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner by driving the proteasomal degradation of cell junction-associated proteins.