Abstract：Objective: To investigate the effect of the interaction between Yes-associated protein 1 (YAP1) and RNA molecule N6-methyladenosine (m6A) modification on the chemosensitivity of gastric cancer (GC). Methods: Cisplatin-resistant AGS/DDP cells and their cisplatin-sensitive parental AGS cells were used as cell models.The expression of methyltransferase-like 3 (METTL3) and YAP1 proteins was analyzed using immunoblotting,and the extent of m6A modification was determined by Poly(A) RNA dot blotting.The influence of METTL3-induced m6A modification on YAP1 translation was assessed using a luciferase reporter gene.The impact of cisplatin treatment on apoptosis in METTL3- or YAP1-knockout AGS/DDP cells was examined by Tunel.A mouse xenograft model was established to study the effect of METTL3 knockout on cisplatin sensitivity in vivo. Results: The expression of m6A methyltransferase METTL3 was elevated in AGS/DDP cells,a cisplatin-resistant subline of GC cells,in comparison to the parental cells.METTL3 increased the m6A modification of YAP1 mRNA in AGS/DDP cells,enhancing its translation efficiency.Conversely,knockout of METTL3 in AGS/DDP cells reduced YAP1 expression and restored cisplatin sensitivity.Cisplatin treatment following METTL3 knockout induced apoptosis in AGS/DDP cells and reduced tumor growth derived from AGS/DDP cells in BALB/c nude mice. Conclusion: METTL3-induced m6A modification plays a significant role in acquired cisplatin resistance by promoting YAP1 upregulation,suggesting that METTL3 may be a potential candidate for targeted chemotherapy in GC.
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2023, Vol. 29 
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