FAT1 knockdown enhances the CSC properties of HNSCC through p-CaMKII-mediated inactivation of the IFN pathway.

FAT atypical cadherin 1 (), which encodes an atypical cadherin-coding protein, has 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 unresolved. In this context, we reported that FAT1 was downregulated in tumor tissues/cells compared with normal tissues/cells and that it was correlated with the clinicopathological features and prognosis of HNSCC. Knockdown of FAT1 enhanced cancer stem cell (CSC) properties and decreased the percentage of apoptotic tumor cells. Mechanistically, FAT1 knockdown increased the phosphorylation levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII), subsequently resulting in diminished interaction between phosphorylated STAT1 and interferon regulatory factor 9 (IRF9), which inactivated the interferon pathway and facilitated the adoption of the malignant phenotype of HNSCC cells. The overexpression of STAT1 and IRF9 alleviated the malignant behavior caused by FAT1 inhibition. In summary, our study reveals the role of FAT1 in suppressing the CSC properties of HNSCC via the CaMKII/STAT1/IRF9 pathway, and that targeting might be a promising treatment for HNSCC.