STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis
Menée sur des lignées cellulaires de carcinome épidermoïde et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant l'accumulation d'une isoforme de p63 dans les cellules cancéreuses, la protéine Stxbp4 favorise la prolifération cellulaire
The N-terminally truncated isoform of p63 (ΔNp63) is overexpressed in some forms of squamous cell carcinoma (SCC). Here we show that the anaphase-promoting complex/cyclosome (APC/C) degradation machinery plays an essential role in regulating the proteolysis of ΔNp63. We report as well that syntaxin-binding protein 4 (Stxbp4) suppresses APC/C-mediated ubiquitination and proteolysis of ΔNp63 and thereby drives the oncogenic potential of SCC. Aberrancies in this newly defined mechanism could account for ΔNp63 overexpression in SCC. These findings suggest that Stxbp4 could be a relevant therapeutic target for SCC detection and treatment. Levels of the N-terminally truncated isoform of p63 (ΔN 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 ΔNp63α through the M–G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to ΔNp63, can suppress the APC/C-mediated proteolysis of ΔNp63. Supporting the physiological relevance, of these interactions, both Stxbp4 and an APC/C-resistant version of ΔNp63α (RL7-ΔNp63α) inhibit the terminal differentiation process in 3D organotypic cultures. In line with this, both the stable RL7-ΔNp63α 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 ΔNp63 in human squamous cell carcinoma (SCC). Our study reveals that Stxbp4 drives the oncogenic potential of ΔNp63α and may provide a relevant therapeutic target for SCC.