4sc-202 and Ink-128 cooperate to reverse the epithelial to mesenchymal transition in OSCC

Treating oral squamous cell carcinoma (OSCC) presents significant challenges due to high rates of treatment resistance, which often lead to tumor recurrence and metastasis to lymph nodes. Therefore, it is crucial to investigate new inhibitors for OSCC. In this study, we aimed to identify drugs that could work alongside histone deacetylase inhibitors to reverse epithelial-to-mesenchymal transition (EMT), inhibit cell migration and invasion, and enhance therapeutic effectiveness. Our results showed that the drug 4sc-202 effectively reversed EMT, significantly reducing cell migration and invasion in vitro, partly by increasing expression of the tumor suppressor gene FoxO1. Additionally, 4sc-202 exhibited a synergistic effect with Ink-128, further inhibiting tumor migration and invasion in vitro. Mechanistically, 4sc-202 promoted FoxO1 expression, while Ink-128 facilitated its nuclear translocation. Our findings suggest that FoxO1 may reverse EMT by interacting with Twist1 in OSCC. In conclusion, we identified a promising combination therapy involving class I histone deacetylase and mTOR complex 1/2 inhibitors, which effectively block EMT in tumor cells by upregulating FoxO1 expression and inhibiting Twist1 transcription. These results have important implications for developing new strategies for the early diagnosis and treatment of OSCC.