KLF5-mediated transcriptional activation of miR-203a inhibits EMT and increases cisplatin sensitivity by targeting SNAI2 in tongue cancer.

Distant metastasis, cancer recurrence, and resistance to chemotherapy together are responsible for poor prognosis and create challenges for effective treatment of tongue squamous cell carcinoma (TSCC) or tongue cancer. Consequently, identifying key molecular regulators that simultaneously modulate tumor progression and drug resistance is crucial to improving therapeutic outcomes. In this study, we investigated hub transcription factors (TFs) that regulate multiple tumorigenic and drug-resistance-associated processes and elucidated their downstream regulatory molecular mechanisms by integrating gene and miRNA expression analyses, pathway enrichment, miRNA target prediction, and several experimental molecular assays in TSCC cell lines, including cisplatin-resistant cells. We identified that KLF5 is significantly downregulated in TSCC, where it functions as a key suppressor of cell migration and epithelial-mesenchymal transition (EMT). Mechanistically, KLF5 transcriptionally activates miR-203a, which suppresses EMT and restores cisplatin sensitivity in resistant TSCC cells by directly targeting SNAI2. Furthermore, the drug efflux transporter ABCC1 is co-expressed with SNAI2, and miR-203a-mediated inhibition of SNAI2 reduced ABCC1 expression, leading to increased cisplatin accumulation, DNA damage, and cell death. Collectively, our findings reveal a KLF5-miR-203a-SNAI2 regulatory axis that modulates EMT and chemoresistance in TSCC, highlighting a potential therapeutic approach to overcome cisplatin resistance.