5-formylcytosine and Neoplasms

Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), resulting in genomic DNA demethylation. Decreased 5-hmC levels have been reported in a variety of cancers, and loss of 5-hmC might be considered an epigenetic hallmark of cancer. However, the prognostic value of decreased 5-hmC in cancers remain controversial. Here, a systematic review was performed by conducting an electronic search of PubMed, EMBASE, Web of Science and the Cochrane Library. Finally, ten studies with a total of 1736 patients with cancer were included in the present study. Negative/low 5-hmC levels were significantly associated with lymph node metastasis [OR=2.20, 95% CI=1.23-3.96, P=0.008] and advanced TNM stage [OR=2.89, 95% CI=1.21-6.92, P=0.017]. More importantly, negative/low 5-hmC levels were significantly associated with poor prognosis of cancer patients [overall survival: HR=1.76, 95% CI=1.41-2.11, P < 0.001; disease free survival: HR=1.28, 95% CI=0.60-1.96, P < 0.001]. The results of this meta-analysis indicate that decreased 5-hmC levels are an indicator of poor survival of cancer patients. Given variability related to ethnicity, cancer types and detection methods, additional well-designed studies with larger sample sizes are required to further confirm our findings.

Topics: 5-Methylcytosine; Cytosine; DNA Methylation; Humans; Lymphatic Metastasis; Neoplasms; Prognosis

5-Methylcytosine and methylated histones have been considered for a long time as stable epigenetic marks of chromatin involved in gene regulation. This concept has been recently revisited with the detection of large amounts of 5-hydroxymethylcytosine, now considered as the sixth DNA base, in mouse embryonic stem cells, Purkinje neurons and brain tissues. The dioxygenases that belong to the ten eleven translocation (TET) oxygenase family have been shown to initiate the formation of this methyl oxidation product of 5-methylcytosine that is also generated although far less efficiently by radical reactions involving hydroxyl radical and one-electron oxidants. It was found as additional striking data that iterative TET-mediated oxidation of 5-hydroxymethylcytosine gives rise to 5-formylcytosine and 5-carboxylcytosine. This survey focuses on chemical and biochemical aspects of the enzymatic oxidation reactions of 5-methylcytosine that are likely to be involved in active demethylation pathways through the implication of enzymatic deamination of 5-methylcytosine oxidation products and/or several base excision repair enzymes. The high biological relevance of the latter modified bases explains why major efforts have been devoted to the design of a broad range of assays aimed at measuring globally or at the single base resolution, 5-hydroxymethylcytosine and the two other oxidation products in the DNA of cells and tissues. Another critical issue that is addressed in this review article deals with the assessment of the possible role of 5-methylcytosine oxidation products, when present in elevated amounts in cellular DNA, in terms of mutagenesis and interference with key cellular enzymes including DNA and RNA polymerases.

Topics: 5-Methylcytosine; Animals; Cytosine; Dioxygenases; DNA; DNA Methylation; DNA Repair; Humans; Models, Biological; Mutagenesis; Neoplasms; Oxidation-Reduction

Methylation of the fifth carbon of cytosine was the first epigenetic modification to be discovered in DNA. Recently, three new DNA modifications have come to light: hydroxymethylcytosine, formylcytosine, and carboxylcytosine, all generated by oxidation of methylcytosine by Ten Eleven Translocation (TET) enzymes. These modifications can initiate full DNA demethylation, but they are also likely to participate, like methylcytosine, in epigenetic signalling per se. A scenario is emerging in which coordinated regulation at multiple levels governs the participation of TETs in a wide range of physiological functions, sometimes via a mechanism unrelated to their enzymatic activity. Although still under construction, a sophisticated picture is rapidly forming where, according to the function to be performed, TETs ensure epigenetic marking to create specific landscapes, and whose improper build-up can lead to diseases such as cancer and neurodegenerative disorders.

Topics: 5-Methylcytosine; Animals; Cytosine; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Gene Expression Regulation; Humans; Neoplasms; Neurodegenerative Diseases; Oxidation-Reduction; Signal Transduction

The importance of eukaryotic DNA methylation [5-methylcytosine (5mC)] in transcriptional regulation and development was first suggested almost 40 years ago. However, the molecular mechanism underlying the dynamic nature of this epigenetic mark was not understood until recently, following the discovery that the TET proteins, a family of AlkB-like Fe(II)/α-ketoglutarate-dependent dioxygenases, can oxidize 5mC to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Since then, several mechanisms that are responsible for processing oxidized 5mC derivatives to achieve DNA demethylation have emerged. Our biochemical understanding of the DNA demethylation process has prompted new investigations into the biological functions of DNA demethylation. Characterization of two additional AlkB family proteins, FTO and ALKBH5, showed that they possess demethylase activity toward N(6)-methyladenosine (m(6)A) in RNA, indicating that members of this subfamily of dioxygenases have a general function in demethylating nucleic acids. In this review, we discuss recent advances in this emerging field, focusing on the mechanism and function of TET-mediated DNA demethylation.

Topics: 5-Methylcytosine; Animals; Cytosine; DNA; DNA Methylation; Escherichia coli; Gene Expression Regulation; Genome; Germ Cells; HEK293 Cells; Humans; Methylation; Mice; Neoplasms; Oxygen; RNA; Stem Cells; Transcriptome

DNA methylation has been linked to aberrant silencing of tumor suppressor genes in cancer, and an imbalance in DNA methylation-demethylation cycles is intimately implicated in the onset and progression of tumors. Ten-eleven translocation (TET) proteins are Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases that successively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thereby mediating active DNA demethylation. In this review, we focus on the pathophysiological role of TET proteins and 5hmC in cancer. We present an overview of loss-of-function mutations and abnormal expression and regulation of TET proteins in hematological malignancies and solid tumors, and discuss the potential prognostic value of assessing TET mutations and 5hmC levels in cancer patients. We also address the crosstalk between TET and two critical enzymes involved in cell metabolism: O-linked β-N-acetylglucosamine transferase (OGT) and isocitrate dehydrogenase (IDH). Lastly, we discuss the therapeutic potential of targeting TET proteins and aberrant DNA methylation in cancer.

Topics: 5-Methylcytosine; Azacitidine; Cytosine; Decitabine; Dioxygenases; DNA Methylation; DNA Modification Methylases; DNA-Binding Proteins; Hematologic Neoplasms; Humans; Isocitrate Dehydrogenase; Mixed Function Oxygenases; Molecular Targeted Therapy; Mutation; Neoplasms; Proto-Oncogene Proteins; Small Molecule Libraries