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Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3-stage (aOR = 2.1, 95%CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR = 2.2, 95%CI: 1.2-4.0) and lower 10-year overall survival (p = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated is oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC. [ABSTRACT FROM AUTHOR]