DNA Methylation can lead to abnormal gene expression. In the present study, we investigated whether the expression of methylated MFSD4A (major facilitator superfamily domain containing 4 A) was downregulated in nasopharyngeal carcinoma (NPC) and whether it is associated with malignant progression and poor prognosis of NPC. Bioinformatic analysis, bisulfite pyrosequencing, quantitative real-time reverse transcription PCR, and western blotting assays were performed to explore the relationship between hypermethylation of MFSD4A and its expression in NPC. The role of MFSD4A in NPC was verified by Cell Cycle Kit 8, transwell assays and flow cytometry in vitro and by animal experiments in vivo. Mass spectrometry, co-immunoprecipitation, and immunofluorescence assays were applied to explore the mechanism by which MFSD4A inhibits NPC. The prognostic significance of MFSD4A or EPHA2 was investigated by immunohistochemical analysis of clinical specimens. Hypermethylation of the promoter region of MFSD4A led to decreased expression of MFSD4A. When MFSD4A expression was upregulated or downregulated, the proliferation, apoptosis, migration, and invasion abilities of NPC cells were altered accordingly. Mechanistically, MFSD4A could specifically bind to and degrade EPH receptor A2 (EPHA2) by recruiting ring finger protein 149 (RNF149), which led to alterations in the EPHA2-mediated PI3K-AKT-ERK1/2 pathway and epithelial-mesenchymal transition (EMT), thereby affecting NPC progression. Clinically, high MFSD4A expression or low-EPHA2 expression was associated with better prognosis for patients with NPC. In all, reduced MFSD4A expression in NPC is caused by promoter hypermethylation. MFSD4A or EPHA2 expression is associated with the malignant biological behavior and prognosis of NPC. MFSD4A is a promising potential therapeutic target for NPC.
© 2022. The Author(s).