FOXD1 Promotes EMT and Cell Stemness of Head and Neck Squamous Cell Carcinoma by Transcriptional Activation of SNAI2

Abstract BackgroundEpithelial-mesenchymal transition (EMT) and cell stemness are implicated in the initiation and progression of head and neck squamous cell carcinoma (HNSCC). Revealing the intrinsic regulatory mechanism may provide effective therapeutic targets for HNSCC.ResultsIn this study, we found Forkhead box D1 (FOXD1) was upregulated in HNSCC when compared with normal samples. Patients with higher FOXD1 expression had poorer overall survival and disease-free survival. Immunohistochemistry results showed that FOXD1 expression was related to the clinical stage and relapse status of HNSCC patients. When knockdown the expression of FOXD1 in CAL27 and SCC25 cells, the migration, invasion, colony formation, sphere formation, and proliferation abilities decreased. Moreover, the EMT and stemness-related markers changed remarkably, which indicated the EMT process and cell stemness were inhibited. Conversely, overexpression of FOXD1 promoted EMT and cell stemness. Further study demonstrated that FOXD1 could bind to the promoter region and activate the transcription of SNAI2. The elevated SNAI2, in turn, affected the EMT and cell stemness. The in vivo study showed FOXD1 overexpressed CAL27 cells possessed stronger tumorigenic ability.ConclusionsOur findings revealed a novel mechanism in regulating EMT and cell stemness, and proposed FOXD1 as a potential marker for diagnosis and treatment of HNSCC.