In this study, we have showed that the protein lysine methyltransferase WHSC1L1 mono-methylates EGFR at lysine K721 in its tyrosine kinase domain, and leads to constitutive enhancement of the RAS-RAF-MEK-ERK pathway through augmentation of phospho-Y1148 and phospho-Y1173 in SCCHN cells even without EGF stimulation. The gene discussed is NSD3; the disease is head and neck squamous cell carcinoma.