N-glycosylation of ACTRIIB enhances protein stability leading to rapid cell proliferation and strong resistance to docetaxel in nasopharyngeal carcinoma.

Abstract

Nasopharyngeal carcinoma (NPC) is a malignant tumor predominantly influenced by Epstein-Barr virus infection and genetic factors. The transforming growth factor-beta (TGF-β) superfamily is implicated in various cellular processes, including tumorigenesis. This study aimed to detect the role of one TGF-β superfamily member activin receptor type IIB (ACTRIIB) in NPC. This study analyzed NPC datasets, including GSE12452, GSE102349, and GSE53819. ACTRIIB expression and N-glycosylation levels were assessed by western blot, real-time PCR, immunofluorescence, and immunohistochemistry in NPC cells and tissues. As indicated by the datasets, ACTRIIB was significantly upregulated in NPC tissues, and the up-regulation was associated with poor prognosis. This study confirmed the N-glycosylation of ACTRIIB primarily at the forty-second amino acid, an asparagine. The N-glycosylation of ACTRIIB promoted the localization of ACTRIIB to the cell membrane and prevented the degradation of the protein by lysosomes, through which ACTRIIB activated the downstream Smard1/2 to promote tumor cell proliferation and invasion. Inhibition of N-glycosylation or knockdown of ACTRIIB resulted in reduced cell proliferation and invasion and increased the cell sensitivity to docetaxel. In conclusion, N-glycosylation of ACTRIIB was a critical post-translational modification that enhanced protein stability and induced membrane localization, which facilitates the functions of ACTRIIB in cell proliferation and invasion in NPC. Inhibition of ACTRIIB N-glycosylation could potentially serve as a therapeutic strategy to improve the efficacy of chemotherapy in NPC.