Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent non-skin cancer in the world. While immunotherapy has revolutionized the standard of care treatment in patients with recurrent/metastatic HNSCC, more than 70% of patients do not respond to this treatment, making the identification of novel therapeutic targets urgent. Recently, research endeavors have focused on how epigenetic modifications may affect tumor initiation and progression of HNSCC. The nuclear receptor binding SET domain (NSD) family of protein methyltransferases NSD1-NSD3 is of particular interest for HNSCC, with NSD1 and NSD3 being amongst the most commonly mutated or amplified genes respectively in HNSCC. Preclinical studies have identified both oncogenic and tumor-suppressing properties across NSD1, NSD2, and NSD3 within the context of HNSCC. The purpose of this review is to provide a better understanding of the contribution of the NSD family of protein methyltransferases to the pathogenesis of HNSCC, underscoring their promise as novel therapeutic targets in this devastating disease.