Regulation of Fascin -1 by Epstein–Barr virus-induced methylation and its encoded Zta in EBV-associated gastric cancer

Abstract Epstein-Barr virus-associated gastric cancer (EBVaGC) represents a distinct subtype of gastric cancer (GC), characterized by promoter hypermethylation of host cell genes induced by Epstein-Barr virus (EBV). Fascin actin-bundling protein 1 (FSCN1) has the ability to induce membrane protrusions and is essential for processes such as cell migration, motility, adhesion, and various cellular interactions. FSCN1 has been found to be highly expressed in multiple tumor cells and tissues and is clinically correlated with the poor prognosis of patients. Although there are studies indicating that FSCN1 is highly expressed in GC cells and tissues, the expression of FSCN1 in EBVaGC and the associated molecular mechanisms remain unexplained. Our study indicates that EBV-induced hypermethylation of FSCN1 promoter leads to the silencing of FSCN1 expression in EBV-positive gastric cancer cells. After inducing EBV reactivation, the expression of FSCN1 was significantly upregulated. We further demonstrated that EBV stimulates FSCN1 expression through direct binding of its lytic protein Zta to FSCN1 promoter. Together, EBV dynamically regulates the expression of FSCN1 through different infection stages, thereby influencing the malignant phenotype and clinical prognosis of gastric cancer, suggesting that FSCN1 is a potential key effector molecule in EBVaGC.