N-glycosylation of ERLIN2 promotes hepatocellular carcinoma progression by enhancing CCNB1 stability.

Hepatocellular carcinoma (HCC) ranks among the most lethal cancers, and its dismal prognosis underscores the urgent need to elucidate the underlying carcinogenic mechanisms. Endoplasmic reticulum lipid rafts associated protein 2 (ERLIN2), an endoplasmic reticulum protein, has been implicated in various malignant tumors. However, its functional role in HCC remains poorly understood. Here, we found elevated ERLIN2 expression and N-glycosylation modification at asparagine 106 (N106) in HCC. We identify site-specific N-glycosylation as a crucial advantage of ERLIN2 that may result in aberrant cancer cell growth. Overexpression of either N-glycosylated ERLIN2 (wild-type, WT) or an asparagine-to-glutamine mutant (N106Q) in HCC cell lines indicated that N106 N-glycosylation of ERLIN2 acts as an important advantage in the tumorigenesis and triggers aberrant cell proliferation, migration, and invasion. Furthermore, we found that E3 ubiquitin ligase membrane-associated ring-CH-type finger protein 6 (MARCHF6) can mediate the ubiquitination degradation of ERLIN2, and this effect is more significant after the N-glycosylation at the N106 site is inhibited. In addition, excessive N-glycosylation at this site enhanced the interaction between ERLIN2 and cyclin B1 (CCNB1), leading to dysregulated CCNB1 expression and further accelerating the progression of HCC. Comprehensive studies confirm that N-glycosylation is a significant post-translational modification of ERLIN2 in HCC, and elucidating this mechanism may pave the way for the development of novel therapeutic strategies in the future.