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

ABSTRACT: Levels of the N-terminally truncated isoform of p63 (?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 ?Np63? through the M-G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to ?Np63, can suppress the APC/C-mediated proteolysis of ?Np63. Supporting the physiological relevance, of these interactions, both Stxbp4 and an APC/C-resistant version of ?Np63? (RL7-?Np63?) inhibit the terminal differentiation process in 3D organotypic cultures. In line with this, both the stable RL7-?Np63? 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 ?Np63 in human squamous cell carcinoma (SCC). Our study reveals that Stxbp4 drives the oncogenic potential of ?Np63? and may provide a relevant therapeutic target for SCC.

SUBMITTER: Rokudai S 

PROVIDER: S-EPMC6003458 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature