In the present study, we characterized the gene expression profile of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, the DNA demethylases TET1, TET2, TET3, and TDG, and the RNA methyltransferase TRDMT1 to gain a more comprehensive insight into the epigenetic regulation of HNSCC aggressiveness and HPV-driven tumorigenesis by DNA and RNA methylation. This evidence concerns the gene TRDMT1 and head and neck squamous cell carcinoma.