The USP28-{triangleup}Np63 axis is a vulnerability of squamous tumours
The transcription factor {Delta}Np63 is a master regulator that establishes epithelial cell identity and is essential for the survival of SCC of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes {Delta}Np63 protein and maintains elevated {Delta}NP63 levels in SCC by counteracting its proteasome-mediated degradation. Interference with USP28 activity by genetic means abolishes the transcriptional identity of SCC cells and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered mouse models establish that both induction and maintenance of lung SCC strictly depend on endogenous USP28. Targeting {Delta}Np63 protein abundance in SCC via inhibition of USP28 therefore is a feasible strategy for the treatment of SCC tumours.\n\nSignificanceSCC depend on {Delta}Np63, and its protein abundance is tightly controlled by the ubiquitin proteasome system. Here, we demonstrate the dependence of SCC on USP28 for various human SCC in vitro and in vivo using murine lung tumour models. As inhibitors for deubiquitylases become available, targeting USP28 is a promising therapeutic strategy.