Systematic screening identifies a TEAD4-S100A13 axis modulating cisplatin sensitivity of oral squamous cell carcinoma cells.

This study aimed to screen prognosis-related S100 protein family members in human paxpillomaviruses (HPV)-negative oral squamous cell carcinoma (OSCC) and their molecular regulations. Bioinformatic screening was conducted based on single-cell RNA-seq data from Puram 2017 dataset and bulk-seq data from the Cancer Genome Atlas (TCGA). HPV-negative OSCC cell lines CAL-27 and SCC-4 were used as in vitro cell models. Among 21 S100 protein family member genes, S100A13 upregulation was associated with unfavorable progression-free survival and disease-specific survival of OSCC patients. Gene Set Enrichment Analysis showed that the higher S100A13 expression group had elevated genes enriched in DNA repair and oxidative phosphorylation. S100A13 knockdown increased cisplatin sensitivity, while its overexpression decreased the sensitivity of CAL-27 and SCC-4 cells. S100A13 gene had complex alternative transcription patterns. ENST00000440685 is one of the major protein-coding transcripts and was the only transcript elevated in the tumor group. TEAD4 could bind to the promoter of ENST00000440685 and increase its transcription. TEAD4 overexpression alleviated the tumor-suppressive effect of cisplatin in terms of colony formation, the expression of apoptotic proteins, and DNA damage. However, S100A13 knockdown partly abrogated the protective effects of TEAD4 overexpression. This study revealed a novel TEAD4-S100A13 axis that might modulate cisplatin sensitivity of OSCC tumor cells.