Clinical significance of DNA methylation mRNA levels of TET family members in colorectal cancer

Abstract

Purpose Ten eleven translocation (TET) enzyme activity is essential for active DNA demethylation in biological processes, and their altered expression has been observed in various malignancies. Therefore, we investigated DNA methylation and mRNA levels of all TETs in colorectal cancer (CRC) patients.MethodsTET mRNA levels were evaluated using quantitative RT-PCR in primary cancerous and histopathologically unchanged colorectal tissues from patients who underwent radical surgical colon resection (n = 113). DNA methylation levels of the TET CpG island were assessed using bisulfite DNA sequencing and high-resolution melting analysis.ResultsWe found reduced transcript levels of TET1, TET2 and TET3 in cancerous tissue compared with their histopathologically unchanged counterparts (p = 0.000011; p = 0.000001; p = 0.00031, respectively). Importantly, multivariate Cox regression analysis revealed favorable overall survival (OS) and disease-free survival (DFS) outcomes for patients with high TET2 mRNA levels in histopathologically unchanged tissue (HROS = 0.091, 95 % CI 0.011–0.77, p = 0.028; HRDFS = 0.21, 95 % CI 0.04–1.06, p = 0.059). Moreover, we found no DNA methylation in the TET2 and TET3 promoter regions in cancerous and histopathologically unchanged tissue. In contrast, we reported TET1 DNA hypermethylation in a small fraction of patients (n = 12/113).ConclusionTo best of our knowledge, our study is the first to investigate TET mRNA levels in a cohort of CRC patients and correlate them with patients’ prognosis. Present study provides the evidence that TET2 mRNA expression may be an independent prognostic factor for disease recurrence and outcome. Additionally, our findings initially indicate the importance of DNA methylation in regulating TET1 expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-014-1901-2) contains supplementary material, which is available to authorized users.

Transcript levels of ten-eleven translocation type 1–3 in cervical cancer and non-cancerous cervical tissues

“…One epigenetic mechanism of DNA methylation consists of cytosine methylation in cytosine-phosphate-guanine (CpG) dinucleotide islands, located in the promoter region of numerous genes (6,11,12). During malignant transformation, CpG islands become hypermethylated, silencing the expression of suppressor genes and leading to a loss in the control of cell proliferation (13,14). By contrast, the hypomethylation of oncogenes increases cell division and enhances the metastasis of cancer cells (14).…”

“…The process of methylation has been well characterized in recent years, but the underlying mechanism of demethylation, particularly during carcinogenesis, remains to be elucidated (6,15,16). Ten-eleven translocation (TET) proteins have an important role in DNA demethylation, with reduced expression observed in various tumors (6,13,(17)(18)(19)(20)(21)(22).…”

“…The TET proteins have been revealed to catalyze the oxidation of 5-mC to 5-hydroxymethylcytosine Transcript levels of ten-eleven translocation type 1-3 in cervical cancer and non-cancerous cervical tissues (5-hmC) (25). Subsequently, 5-hmC is oxidized to 5-formylocytosine (5-fC) and 5-carboxycytosine (5-caC), eventually converting 5-mC to cytosine (13,17,26). This transformation may contribute to unlocking the promoter regions of suppressor genes and facilitating the development of cancer (8,13,16).…”

“…Subsequently, 5-hmC is oxidized to 5-formylocytosine (5-fC) and 5-carboxycytosine (5-caC), eventually converting 5-mC to cytosine (13,17,26). This transformation may contribute to unlocking the promoter regions of suppressor genes and facilitating the development of cancer (8,13,16). Low TET expression levels are correlated with decreased 5-hmC levels in malignant tissues and with clinicopathological features in various primary cancer tissues (13,17,20,22,27).…”

“…This transformation may contribute to unlocking the promoter regions of suppressor genes and facilitating the development of cancer (8,13,16). Low TET expression levels are correlated with decreased 5-hmC levels in malignant tissues and with clinicopathological features in various primary cancer tissues (13,17,20,22,27). However, little is understood regarding the levels of TET expression in cervical cancerous and non-cancerous tissue.…”