Fat1 suppresses the CSCs properties through CaMKII-mediated activation of the IFN pathway

Abstract

Abstract FAT atypical cadherin 1 (Fat1), which encodes an atypical cadherin-coding protein, exhibits a high mutation rate and is commonly regarded as a tumor-suppressor gene in head and neck squamous cell carcinoma (HNSCC). Nonetheless, the potential regulatory mechanisms by which Fat1 influences the progression of HNSCC remain an unresolved enigma. In this context, we reported FAT1 was down-regulated in tumor tissues/cells when compared to the normal tissues/cells and correlated with the clinicopathological features and prognosis of HNSCC. Knockdown of FAT1 enhanced the CSCs properties and decreased the apoptosis rate of tumor cells. Mechanically, FAT1 knockdown increased the phosphorylation levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII), subsequently resulting in a diminished interaction between phosphorylated STAT1 and interferon regulatory factor 9 (IRF9), which inactivated the interferons pathways and facilitated the malignant phenotype of HNSCC cells. Overexpression of STAT1 and IRF9 alleviated the malignant behavior caused by FAT1 inhibition. In summary, our study unveils the role of FAT1 in suppressing the CSCs properties of HNSCC via the CaMKII /STAT1/IRF9 pathway and targeting FAT1 might be a promising treatment for HNSCC.