Understanding the Roles of the NSD Protein Methyltransferases in Head and Neck Squamous Cell Carcinoma

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.

Keywords: HNSCC; HPV-negative; HPV-positive; NSD; head and neck squamous cell carcinoma; protein methyltransferases.

Figure 1

Reported mechanisms of action of the NSDs in HPV-negative HNSCC. (a) Inactivating mutations of NSD1 in HPV-negative HNSCC induce decreased levels of H3K36me2, global DNA hypomethylation and increased levels of H3K27me3, leading to differentiation arrest, increased sensitivity to cisplatin, and a “cold” immune phenotype. (b) NSD2 in HNSCC. (i) NSD2 dimethylates H3K36, leading to NIMA-related kinase 7 (NEK7) upregulation to promote cytokinesis. (ii) NSD2 monomethylates H1K85, promoting pathways related to cell proliferation and upregulating OCT4, a stemness factor. (c) NSD3 in HNSCC. (i) NSD3 dimethylates H3K36, leading to CDC6 and CDK2 upregulation and promotion of G1-S phase progression. (ii) NSD3 methylates epidermal growth factor receptor (EGFR) at lysine 721, increasing interaction with PCNA to enhance DNA synthesis and promote cell cycle progression.