PAX9 activates autophagy through a transcription-dependent mechanism, promoting EGFR degradation to restrict cell survival in oral cancer

Background PAX9 (paired box 9) gene, a transcription factor belonging to the PAX family, is associated with craniofacial development. Dysregulation of PAX9 is associated with oral squamous cell carcinoma (OSCC), and its functional regulation in OSCC remains unknown.Methods PAX9 expression was evaluated in human OSCC tissues and a DMBA-induced hamster oral carcinogenesis model, and its functional role in cell death and autophagy was assessed using PAX9 overexpression and PAX9 mutants in OSCC. Autophagy, lysosomal activity, apoptosis, EGFR degradation, and chemosensitivity were analysed in vitro and in an OSCC xenograft model.Results Overexpression of PAX9 activated autophagy and enhanced lysosomal function through a transcription-dependent mechanism, thereby inducing apoptosis in OSCC. Mutations at L27P and I29T in PAX9 blocked autophagy and restored cell viability in OSCC. Interestingly, PAX9 was shown to activate lethal autophagy, which degrades EGFR, thereby inducing cell death and chemosensitisation in OSCC. Moreover, PAX9 expression decreased in higher-grade human oral cancers and in DMBA-induced hamster oral carcinogenesis, and in vitro exposure to carcinogens reduced PAX9 while increasing DNMT1, suggesting that DNA methylation may regulate PAX9 during oral carcinogenesis.Conclusion PAX9 activates lethal autophagy, promoting EGFR degradation and apoptosis in OSCC, highlighting its tumour-suppressive potential and therapeutic relevance.