Clinical epigenetics · 2026
Arecoline-induced EV-mediated ZNF582 hypermethylation drives IFIT1-PD-L1 immune evasion in oral squamous cell carcinoma.
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Ko Hui-Hsin, Peng Hsin-Hui, Chiang Chun-Pin, Kao Hsiang-Fong, Lin Hung-Ying, Kuo Mark Yen-Ping, Cheng Shih-Jung
Аннотация
BACKGROUND: This study examined the role of arecoline-induced zinc finger protein 582 (ZNF582) methylation via extracellular vesicles (EVs) in oral squamous cell carcinoma (OSCC) and its effect on PD-L1 expression through the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) pathway.
MATERIALS AND METHODS: EVs were isolated from SAS and TW2.6 cancer cell lines using ultracentrifugation and characterized using electron microscopy. ZNF582 methylation and protein expression were assessed, with stemness and epithelial-mesenchymal transition (EMT) markers analyzed via Western blotting. T cell populations were evaluated using flow cytometry.
RESULTS: Arecoline-induced ZNF582 methylation via EVs reduced protein expression. ZNF582 knockdown promoted OSCC proliferation, migration, stemness, and EMT, and increased PD-L1 expression, aiding immune evasion via IFIT1. PD-L1 expression was linked to lower CD4+/CD8 + T cell ratios in OSCC patients.
CONCLUSION: Arecoline-induced ZNF582 hypermethylation via EVs promotes immune evasion through IFIT1, suggesting a potential therapeutic target for OSCC treatment.
CLINICAL RELEVANCE: Targeting the EV-mediated ZNF582-IFIT1-PD-L1 pathway may offer new therapeutic strategies for immune modulation in OSCC patients, especially those with a history of areca nut exposure.
MATERIALS AND METHODS: EVs were isolated from SAS and TW2.6 cancer cell lines using ultracentrifugation and characterized using electron microscopy. ZNF582 methylation and protein expression were assessed, with stemness and epithelial-mesenchymal transition (EMT) markers analyzed via Western blotting. T cell populations were evaluated using flow cytometry.
RESULTS: Arecoline-induced ZNF582 methylation via EVs reduced protein expression. ZNF582 knockdown promoted OSCC proliferation, migration, stemness, and EMT, and increased PD-L1 expression, aiding immune evasion via IFIT1. PD-L1 expression was linked to lower CD4+/CD8 + T cell ratios in OSCC patients.
CONCLUSION: Arecoline-induced ZNF582 hypermethylation via EVs promotes immune evasion through IFIT1, suggesting a potential therapeutic target for OSCC treatment.
CLINICAL RELEVANCE: Targeting the EV-mediated ZNF582-IFIT1-PD-L1 pathway may offer new therapeutic strategies for immune modulation in OSCC patients, especially those with a history of areca nut exposure.
Предметные рубрики MeSH
ArecolineKruppel-Like Transcription FactorsImmune EvasionDNA MethylationCarcinoma, Squamous CellMouth NeoplasmsHumansCell Line, TumorNeoplasm MetastasisPrognosisMaleFemaleMiddle AgedB7-H1 AntigenExtracellular VesiclesRNA-Binding ProteinsEpithelial-Mesenchymal TransitionCD4-Positive T-LymphocytesAdaptor Proteins, Signal TransducingCD8-Positive T-Lymphocytes