Mechanistically, SMYD3 binds to and regulates the transcription of specific cell cycle- and EMT-related genes, such as SMAD2, SMAD4, PPIB, THBS2, FBN1, LAMA1, ZEB1 and CDH1, ultimately promoting the proliferative and invasive potential of HPV-negative HNSCC cells. This evidence concerns the gene SMAD4 and head and neck squamous cell carcinoma.