Disruption of transforming growth factor-beta signaling by five frequently methylated genes leads to head and neck squamous cell carcinoma pathogenesis

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates in advanced stages. To facilitate timely diagnosis and improve outcome, early detection markers (e.g., DNA methylation) are crucial for timely cancer diagnosis. In a recent publication, an epigenome-wide screen revealed a set of genes that are commonly methylated and downregulated in head and neck cancers (SEPT9, SLC5A8, FUSSEL18, EBF3, and IRX1). Interestingly, these candidates are potentially involved in the transforming growth factor-beta (TGF-beta) signaling pathway, which is often disrupted in HNSCC. Therefore, we sought to determine coordinated epigenetic silencing of these candidate genes in HNSCC as potential key disruptors of TGF-beta signaling, which could ultimately result in HNSCC progression. Through immunoprecipitation studies, all five of the investigated candidate genes were found to interact with components of the TGF-beta pathway. Overexpression of SLC5A8, EBF3, and IRX1 resulted in decreased mitotic activity and increased apoptosis. In addition, EBF3 was found to increase p21 promoter activity, and SMAD2 significantly increased IRX1 promoter activity. These findings are significant because they reveal a set of genes that interact with components of the TGF-beta pathway, and their silencing via methylation in HNSCC results in coordinated decrease in apoptosis, increased proliferation, and decreased differentiation.