HSF1 activates the FOXO3a-ΔNp63α-CDK4 axis to promote head and neck squamous cell carcinoma cell proliferation and tumor growth.

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers worldwide. Heat shock factor 1 (HSF1) is a conserved transcriptional factor that plays a critical role in maintaining cellular proteostasis. However, the role of HSF1 in HNSCC development remains largely unclear. Here, we report that HSF1 promotes forkhead box protein O3a (FOXO3a)-dependent transcription of ΔNp63α (p63 isoform in the p53 family; inhibits cell migration, invasion, and metastasis), which leads to upregulation of cyclin-dependent kinase 4 (CDK4) expression and HNSCC tumor growth. Ablation of HSF1 or treatment with KRIBB11, a specific pharmacological inhibitor of HSF1, significantly suppresses ΔNp63α expression and HNSCC tumor growth. Clinically, the expression of HSF1 is positively correlated with the expression of ΔNp63α in HNSCC tumors. Together, this study demonstrates that the HSF1-ΔNp63α pathway is critically important for HNSCC tumor growth.