Mechanism of Monocarboxylate Transporter 1 and Its Methylation in Nasopharyngeal Carcinoma Pathogenesis.

Abstract

Objective: This study explores the role of monocarboxylate transporter 1 (MCT1) in nasopharyngeal carcinoma (NPC) metastasis and its regulation via DNA methyltransferase 3B (DNMT3B)-mediated methylation, to identify therapeutic targets for NPC. Methods: MCT1/DNMT3B expression was analyzed in NPC (n = 30) and normal tissues (n = 30) using quantitative polymerase chain reaction (qPCR) and immunohistochemistry. DNMT3B overexpression plasmids were transfected into NPC cells to assess MCT1 expression and promoter methylation via bisulfite sequencing PCR. Luciferase and chromatin immunoprecipitation (ChIP) assays identified DNMT3B-MCT1 promoter interactions. Migration/invasion assays and Western blot evaluated functional impacts of MCT1 silencing on metastasis-related pathways. Bioinformatic validation utilized GEO datasets. Results: MCT1 mRNA/protein levels were significantly elevated in NPC versus normal tissues (***p < 0.001), whereas DNMT3B was downregulated. DNMT3B overexpression reduced MCT1 expression (*p < 0.05) and increased MCT1 promoter methylation (**p < 0.01). Luciferase assays revealed that DNMT3B suppressed wild-type MCT1 promoter activity, dependent on an 80 bp CpG island (**p < 0.01). ChIP confirmed DNMT3B enrichment at hypermethylated MCT1 promoter regions (**p < 0.01). MCT1 silencing inhibited NPC cell migration/invasion (*p < 0.05) and downregulated p-AKT, p-mTOR, and p-NFκB (*p < 0.05). High MCT1 correlated with Epstein-Barr virus (EBV)-associated EBNA1BP2 (**p < 0.01), but not PD-L1 markers. DNMT3B inversely correlated with MCT1 (*p < 0.05) and was upregulated in advanced-stage NPC (Stage III + IV vs. I + II, ***p < 0.001), indicating stage-specific epigenetic dysregulation. Conclusion: MCT1 promotes NPC metastasis via NF-κB and PI3K/AKT/mTOR pathways, regulated by DNMT3B-driven promoter methylation. The MCT1-DNMT3B axis, linked to EBV-associated metabolic reprogramming, represents a prognostic biomarker and therapeutic target for advanced NPC.