Nicastrin Regulates Cutaneous Squamous Cell Carcinoma Progression Through the MAPK/ERK Signalling

Cutaneous squamous cell carcinoma (cSCC) is among the most common epithelial malignancies. Although cSCC arising in long-standing acne inversa (AI) lesions is rare, it is a severe and clinically important complication of AI. Approximately one-third of patients with AI harbour loss-of-function mutations in NCSTN. Whether NCSTN loss contributes to cSCC development remains unclear. To address this, we first examined its expression pattern in cSCC tissues. Interestingly, NCSTN expression was significantly decreased in cSCC tissues by immunohistochemistry (IHC) and Western blotting. Furthermore, loss of NCSTN promoted cSCC cell proliferation and migration in vitro and tumour growth in vivo. Proteomic analysis revealed that NCSTN deficiency promoted cell proliferation through activation of the MAPK/ERK signalling pathway, accompanied by reduced CLDN3 expression and alterations in cell-adhesion-related pathways. To validate the functional relevance of this signalling axis in vivo, we treated NCSTN-knockdown tumour-bearing mice with the ERK inhibitor SCH772984, which effectively suppressed tumour growth. Collectively, these findings demonstrate that loss of NCSTN drives cSCC progression through activation of MAPK/ERK signalling, and identify ERK signalling as a potential therapeutic vulnerability in NCSTN-deficient cSCC.