CERS6 promotes esophageal squamous cell carcinoma proliferation by increasing the stability of RPN1

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis because it is typically diagnosed at a moderate or advanced stage. Investigating the precise molecular mechanism of ESCC pathogenesis is essential for developing new therapeutic strategies. In this study, we demonstrated that ceramide synthase 6 (CERS6) was overexpressed and correlated with a worse prognosis in ESCC. Moreover, CERS6 promoted ESCC cell proliferation in vitro and in vivo. Mechanistically, CERS6 sustained the stability of ribophorin 1 (RPN1) by inhibiting its ubiquitination. Subsequently, CERS6 reduced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) by activating the RPN1-inositol-requiring enzyme 1 (IRE1)-X-box binding protein 1 (XBP1) signaling pathway. Interestingly, the antisense oligonucleotides (ASOs) targeting CERS6 inhibited the growth of ESCC through the RPN1-IRE1-XBP1 signaling pathway. Collectively, our study reveals an unprecedented function and mechanism of CERS6, which is distinct from ceramide synthases, in the development of ESCC, highlighting its potential as a promising therapeutic target.