Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas.

Abstract

The recent identification of isocitrate dehydrogenase 1 (IDH1) gene mutations in gliomas stimulated various studies to explore the molecular consequences and the clinical implications of such alterations. The Cancer Genome Atlas Research Network showed evidence for a CpG island methylator phenotype in glioblastomas that was associated with IDH1 mutations. These alterations were associated with the production of the oncometabolite, 2-hydroxyglutarate, that inhibits oxygenases [ie, ten-eleven translocation (TET) enzymes involved in the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC)]. We investigated 60 gliomas for 5hmC presence, 5-methylcytosine content, TET1 expression, and IDH1 mutation to gain insight into their relationships on a histological level. Of gliomas, 61% revealed no immunoreactivity for 5hmC, and no correlation was observed between IDH1 mutations and loss of 5hmC. Interestingly, expression of TET1 showed remarkable differences regarding overall protein levels and subcellular localization. We found a highly significant (P = 0.0007) correlation between IDH1 mutations and nuclear accumulation of TET1, but not with loss of 5hmC. Of 5hmC-negative gliomas, 70% showed either exclusive or dominant cytoplasmic expression, or no detectable TET1 protein (P = 0.0122). Our data suggest that the loss of 5hmC is a frequent event in gliomas, independent of IDH1 mutation, and may be influenced by the nuclear exclusion of TET1 from the nuclei of glioma cells.

• Authors: Tim Müller, Marco Gessi, Anke Waha, Lukas Jan Isselstein, Daniel Luxen, Dorothee Freihoff, Johannes Freihoff, Albert Becker, Matthias Simon, Jennifer Hammes, Dorota Denkhaus, Anja zur Mühlen, Torsten Pietsch, Andreas Waha
• Journal: The American journal of pathology (Am J Pathol) Vol. 181 Issue 2 Pg. 675-83 (Aug 2012) ISSN: 1525-2191 [Electronic] United States
• PMID: 22688054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Proto-Oncogene Proteins
• RNA, Messenger
• Tumor Suppressor Proteins
• 5-hydroxymethylcytosine
• 5-Methylcytosine
• Cytosine
• Mixed Function Oxygenases
• TET1 protein, human
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Dioxygenases
• TET2 protein, human
• DNA Modification Methylases
• MGMT protein, human
• Mitogen-Activated Protein Kinase Phosphatases
• DUSP4 protein, human
• Dual-Specificity Phosphatases
• DNA Repair Enzymes

Topics

• 5-Methylcytosine (metabolism)
• Brain Neoplasms (enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytosine (analogs & derivatives, metabolism)
• DNA Methylation (genetics)
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Dioxygenases
• Dual-Specificity Phosphatases (genetics)
• Female
• Gene Expression Regulation, Enzymologic
• Glioblastoma (enzymology, genetics, pathology)
• Glioma (enzymology, genetics, pathology)
• Humans
• Immunohistochemistry
• Isocitrate Dehydrogenase (genetics, metabolism)
• Male
• Mitogen-Activated Protein Kinase Phosphatases (genetics)
• Mixed Function Oxygenases
• Mutation (genetics)
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Sequence Analysis, DNA
• Subcellular Fractions (metabolism)
• Tumor Suppressor Proteins (genetics)