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

Cancer Res. 2009 Dec 15;69(24):9301-5. doi: 10.1158/0008-5472.CAN-09-3073.


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.

MeSH terms

  • Apoptosis / physiology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Differentiation / physiology
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • DNA Methylation*
  • Disease Progression
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Monocarboxylic Acid Transporters
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Septins
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*


  • Cation Transport Proteins
  • Cytoskeletal Proteins
  • Homeodomain Proteins
  • IRX1 protein, human
  • MAPRE3 protein, human
  • Microtubule-Associated Proteins
  • Monocarboxylic Acid Transporters
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • SKOR2 protein, human
  • SLC5A8 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • GTP-Binding Proteins
  • SEPTIN9 protein, human
  • Septins