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4sc-202 and Ink-128 cooperate to reverse the epithelial to mesenchymal transition in OSCC
Xi Yang1, Tianyu Sun1, Yajing Zhao1
1Department of Periodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China.
Abstract:
Treatment of oral squamous cell carcinoma remains a challenge due to a high incidence of treatment resistance, which is followed by tumor recrudescence and metastasis to the lymph nodes. Thus, it is important to explore novel inhibitors of OSCC. Here, we aimed to identify drugs that may cooperate with histone deacetylase inhibitors to reverse the EMT, inhibit EMT and cell migration and invasion, and contribute to therapeutic efficacy. We found that treatment with 4sc-202 potently reversed the EMT and thereby inhibited cell migration and invasion in vitro, in part by inducing expression of the FoxO1 tumor-suppressor gene. Furthermore, 4sc-202 also synergized with Ink-128 to inhibit tumor migration and invasion in vitro. Mechanistically, 4sc-202 induced FoxO1 expression, whereas Ink-128 promoted nuclear translocation of FoxO1. Our findings indicated that FoxO1 might reverse the EMT by interacting with Twist1 in OSCC. In conclusion, we identified an effective combination therapy involving class I histone deacetylase and mammalian target of rapamycin complex 1/2 inhibition that effectively blocked the EMT of tumor cells by upregulating FoxO1 expression to inhibit Twist1 transcription. These data have implications for developing new targets for early diagnosis and treatment of OSCC.
Insights
Researchers identified a novel combination therapy for oral squamous cell carcinoma (OSCC). This treatment, involving histone deacetylase and mTOR inhibitors, targets epithelial-mesenchymal transition (EMT) by upregulating the FoxO1 tumor suppressor, offering new therapeutic strategies for OSCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Oral squamous cell carcinoma (OSCC) presents treatment challenges due to resistance, recurrence, and metastasis.
- Developing novel therapeutic strategies is crucial for improving OSCC patient outcomes.
Purpose of the Study:
- To identify drugs that synergize with histone deacetylase (HDAC) inhibitors to reverse epithelial-mesenchymal transition (EMT) in OSCC.
- To explore novel therapeutic targets for OSCC by investigating drug combinations that inhibit tumor cell migration and invasion.
Main Methods:
- In vitro studies using OSCC cell lines to evaluate drug effects on EMT, cell migration, and invasion.
- Investigated the molecular mechanisms involving the FoxO1 tumor suppressor gene and its interaction with Twist1.
- Assessed the synergistic effects of 4sc-202 (HDAC inhibitor) and Ink-128 (mTOR inhibitor) on OSCC cells.
Main Results:
- 4sc-202 treatment reversed EMT and inhibited OSCC cell migration and invasion by inducing FoxO1 expression.
- 4sc-202 and Ink-128 demonstrated synergistic effects in inhibiting tumor cell migration and invasion.
- FoxO1 was found to interact with Twist1, potentially reversing EMT in OSCC.
Conclusions:
- A combination therapy of class I HDAC and mTORC1/2 inhibition effectively blocks OSCC cell EMT.
- Upregulation of FoxO1 expression and inhibition of Twist1 transcription are key mechanisms.
- These findings suggest potential new targets for early diagnosis and treatment of OSCC.
