The E3 ligase TRIM21 promotes progression of pancreatic ductal adenocarcinoma by down-regulating TAp63α and derepressing IL20RB

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and frequently has mutations in the transcription factor p53. TAp63α is a member of the p53 protein family that is generally tumor suppressive in various other p53-mutant or p53-deficient cancers. Here, we found that TAp63α inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and migration in several p53-mutant PDAC cell lines. TAp63α transcriptionally repressed IL20RB (which encodes a subunit of the interleukin-20 receptor), potentially by inducing the methylation of its promoter. However, mutations in p53 or KRAS that are common in PDAC increased the abundance of the E3 ligase TRIM21, which promoted the ubiquitin-dependent degradation of TAp63α. Thus, the degradation of TAp63α enabled increases in IL20RB expression and formation of IL-20 receptors, resulting in the activation of downstream JAK1-STAT3 signaling that stimulated the proliferation, EMT, migration, and in vivo metastatic seeding of PDAC cells. Our findings identify a signaling axis involving TRIM21, TAp63α, and IL-20RB in PDAC progression.