THBS1 upregulation by KLF7 in hypopharyngeal squamous cell carcinoma contributes to lung metastasis through the p38 MAPK signaling.

This study aimed to analyze the specific role of thrombospondin-1 (THBS1) in hypopharyngeal squamous cell carcinoma (HPSCC) and its mechanism. The expression of histone deacetylase 6 (HDAC6), Kruppel-like factor 7 (KLF7), and THBS1 in the tumor and peritumor tissues of patients with HPSCC, HPSCC cells, and human oral keratinocytes was examined. The function of the HDAC6/KLF7/THBS1/p38 MAPK axis in HPSCC cells was explored using lentivirus-mediated genetic interventions in combination with EdU, colony formation, wound healing, Transwell assays, and Western blot assays. An in vivo lung metastasis model in nude mice was constructed by the tail vein injection of FaDu cells. HDAC6 expression was significantly downregulated in HPSCC, losing the removal capacity of H3K9ac marks at the KLF7 promoter, leading to the upregulation of KLF7, which in turn induced THBS1 transcription to activate p38 MAPK signaling and promote the epithelial-mesenchymal transition (EMT) and lung metastasis of HPSCC cells. These findings indicate that HDAC6 hinders KLF7/THBS1/p38 MAPK axis transduction and curtails HPSCC malignant progression by impairing EMT.