5-Hydroxymethylcytosine and ten-eleven translocation dioxygenases in head and neck carcinoma

Abstract

Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage (P = 0.032) and recurrence (P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136-4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC.

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

“…Although DNA methylation and its mechanism are well studied, DNA hypomethylation and demethylation are poorly understood in HNSCC (8,17). In a previous study, we showed that altered levels of 5-hmC were associated with tumorigenesis, and that lower 5-hmC levels were correlated with reduced survival (16). On the other hand, the current study is the rst to examine LINE-1 hypomethylation levels and 5-hmC levels in HNSCC.…”

“…Several studies have also shown that 5-hmC is an intermediate of DNA demethylation (25). Immuno-based assays are the most commonly used, including ELISA, and these methods utilize available antibodies speci c to 5-hmC to avoid crossreactivity with 5-mC and unmethylated cytosine (16). Moreover, 5-hmC depletion could signi cantly contribute to genome instability and inaccurate chromosome segregation, perhaps explaining the correlation between low 5-hmC levels and cancer (26).…”

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

“…Although DNA methylation and its mechanism are well studied, DNA hypomethylation and demethylation are poorly understood in HNSCC (8,17). In a previous study, we showed that altered levels of 5-hmC were associated with tumorigenesis, and that lower 5-hmC levels were correlated with reduced survival (16). However, the current study is the rst to examine LINE-1 hypomethylation levels and 5-hmC levels in HNSCC.…”

“…Several studies have also shown that 5-hmC is an intermediate of DNA demethylation (25). Immuno-based assays are the most commonly used, including ELISA, and these methods utilize available antibodies speci c to 5-hmC to avoid crossreactivity with 5-mC and unmethylated cytosine (16). Moreover, 5-hmC depletion could signi cantly contribute to genomic instability and inaccurate chromosome segregation, perhaps explaining the correlation between low 5-hmC levels and cancer (26).…”

DNA hydroxymethylation is associated with disease severity and persists at enhancers of oncogenic regions in multiple myeloma

“…In solid tumors, 5hmC is depleted compared to normal tissue [ 20 ] and some studies show that a lower 5hmC level is associated with poorer outcome [ 21 – 23 ]. When 5hmC is depleted, the mark is lost at genic regions, particularly around transcription start sites (TSS) and in gene bodies [ 24 ].…”