STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis

Levels of the N-terminally truncated isoform of p63 (Delta N p63), well documented to play a pivotal role in basal epidermal gene expression and epithelial maintenance, need to be strictly regulated. We demonstrate here that the anaphase-promoting complex/cyclosome (APC/C) complex plays an essential role in the ubiquitin-mediated turnover of Delta Np63 alpha through the M-G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to Delta Np63, can suppress the APC/C-mediated proteolysis of Delta Np63. Supporting the physiological relevance, of these interactions, both Stxbp4 and an APC/C-resistant version of Delta Np63 alpha (RL7-Delta Np63 alpha) inhibit the terminal differentiation process in 3D organotypic cultures. In line with this, both the stable RL7-Delta Np63 alpha variant and Stxbp4 have oncogenic activity in soft agar and xenograft tumor assays. Notably as well, higher levels of Stxbp4 expression are correlated with the accumulation of Delta Np63 in human squamous cell carcinoma (SCC). Our study reveals that Stxbp4 drives the oncogenic potential of Delta Np63 alpha and may provide a relevant therapeutic target for SCC.