We demonstrated that PRDM6 expression occurs almost exclusively in tumor cells of clinical HNSCC tissues and that PRDM6 promotes proliferation and growth of HNSCC tumor cells in vitro while suppressing expression of anti-tumor ISGs (ISG15, IFITM1) by both loss- and gain-of-function approaches. The gene discussed is ISG15; the disease is head and neck squamous cell carcinoma.