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Our research investigates the role of the YAP1-PPFIBP2 axis in the epithelial-mesenchymal transition (EMT) and its subsequent impact on invasion and migration in head and neck squamous cell carcinoma (HNSCC). Utilizing both in vitro assays and genomic analyses, we demonstrate that YAP1 upregulates EMT by suppressing PPFIBP2/liprin-β2 expression. This regulatory pathway contributes to enhanced invasiveness and correlates with poorer prognostic outcomes in HNSCC. We specifically knocked down YAP1 in SNU1041 and SCC9 cell lines using siRNA, resulting in reduced invasion and migration. These effects were reversed by subsequent administration of siPPFIBP2. In contrast, overexpression of YAP1 in SCC25 cells led to increased EMT marker activity and enhanced invasive behavior, supporting the functional role of this axis. Importantly, pharmacological inhibition of YAP1 using CA3 led to a notable decrease in EMT markers, invasion, and migration, suggesting that blocking the YAP1-PPFIBP2 axis may serve as an effective therapeutic strategy in HNSCC. In conclusion, our study identifies the YAP1-PPFIBP2 interaction as a crucial mediator of tumor aggressiveness in HNSCC, offering new insight into metastatic progression and highlighting a promising target for therapeutic intervention.