Frequently Methylated Tumor Suppressor Genes in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive cancer. In advanced stages, the patient has poor chances of receiving effective treatment, and survival rates are low. To facilitate timely diagnosis and improve treatment, elucidation of early detection markers is crucial. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable mark. A genome-wide screen using Restriction Landmark Genomic Scanning found a set of genes that are most commonly methylated in head and neck cancers. Five candidate genes: septin 9 (SEPT9), sodium-coupled monocarboxylate transporter 1 (SLC5A8), functional smad-suppressing element on chromosome 18 (FUSSEL18), early B-cell factor 3 (EBF3), and iroquois homeobox 1 (IRX1) were methylated in 27% to 67% of the HNSCC patient samples tested. Furthermore, f50% of the methylated tumor samples shared methylation between two of the five genes (most commonly between EBF3 and IRX1), and 15% shared methylation between three of the five genes. Expression analysis revealed candidate gene down-regulation in 25% to 93% of the HNSCC samples, and 5-aza-2 ¶-deoxycytidine treatment was able to restore expression in at least 2 of 5 HNSCC cell lines for all of the genes tested. Overexpression of the three most frequently down-regulated candidates, SLC5A8, IRX1, and EBF3, validated their tumor suppressor potential by growth curve analysis and colony formation assay. Interestingly, all of the candidates identified may be involved in the transforming growth factor B signaling pathway, which is often disrupted in HNSCC. [Cancer Res 2008;68(12):4494-9]

Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma

“…These experiments revealed that restoring IRX1 can reduce growth and invasion of gastric carcinoma both in vitro and in vivo. The tumor suppressing function of the IRX1 gene was also confirmed by Bennett et al (2008) recently. They found that introducing IRX1 expression in squamous cell carcinoma of the head and neck disclosed the gene's tumor suppressor potential.…”

LINE-1 and Alu Methylation Patterns in Lymph Node Metastases of Head and Neck Cancers

“…Head and neck squamous cell carcinoma (HNSCC) is one of the most serious health problems, ranking as the sixth most common cancer worldwide (Bennett, 2008). Metastasis from these cancers can be fatal (Manikantan, 2012).…”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

“…[52][53][54] Although many of the novel genes we identified have not been previously reported in bladder cancer, their inappropriate methylation, accompanied with gene-silencing, has been reported in the context of other tumor types and suggests potential roles as tumor suppressor genes. 55,56,57 To determine associations between methylation and gene expression, we confined our studies to genes showing frequent and/or high mean levels of methylation. For the majority of gene-transcripts we investigated, promoter methylation was negatively correlated with reduced transcript expression, although not significantly so (data not shown).…”