We investigated the effects of three EZH2 pathway inhibitors: two S-adenosylmethionine (SAM)-competitive inhibitors (GSK-343 and EPZ-5687) and an S-adenosylhomocysteine (SAH)-hydrolase inhibitor (DZNeP) in HPV-positive (SCC-47 and SCC-104) and HPV-negative (SCC-1 and SCC-9) HNSCC cell lines. This evidence concerns the gene EZH2 and head and neck squamous cell carcinoma.