HSF1 activates the FOXO3a-?Np63a-CDK4 axis to promote head and neck squamous cell carcinoma cell proliferation and tumour 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 delta Np63 alpha (p63 isoform in the p53 family; inhibits cell migration, invasion, and metastasis), which leads to upregulation of cyclin-dependent kinase 4 expression and HNSCC tumour growth. Ablation of HSF1 or treatment with KRIBB11, a specific pharmacological inhibitor of HSF1, significantly suppresses DNp63a expression and HNSCC tumour growth. Clinically, the expression of HSF1 is positively correlated with the expression of delta Np63 alpha in HNSCC tumours. Together, this study demonstrates that the HSF1-delta Np63 alpha pathway is critically important for HNSCC tumour growth.