[en] Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in glioma tissue compared with normal brain, and that higher levels of 5-hmC are associated with improved patient survival. DNA demethylation is enzymatically driven by the ten-eleven translocation (TET) dioxygenases that require ascorbate as an essential cofactor. There is limited data on ascorbate in gliomas and the relationship between ascorbate and 5-hmC in gliomas has never been reported. Clinical glioma samples (11 low-grade, 26 high-grade) were analysed for ascorbate, global DNA methylation and hydroxymethylation, and methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Low-grade gliomas contained significantly higher levels of ascorbate than high-grade gliomas (p = 0.026). Levels of 5-hmC were significantly higher in low-grade than high-grade glioma (p = 0.0013). There was a strong association between higher ascorbate and higher 5-hmC (p = 0.004). Gliomas with unmethylated and methylated MGMT promoters had similar ascorbate levels (p = 0.96). One mechanism by which epigenetic modifications could occur is through ascorbate-mediated optimisation of TET activity in gliomas. These findings open the door to clinical intervention trials in patients with glioma to provide both mechanistic information and potential avenues for adjuvant ascorbate therapy.
Disciplines :
Oncology
Author, co-author :
Crake, Rebekah ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory ; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Burgess, Eleanor R; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Wiggins, George A R; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Magon, Nicholas J; Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Das, Andrew B; Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand ; Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
Vissers, Margreet C M; Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Morrin, Helen R; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand ; Cancer Society Tissue Bank, University of Otago Christchurch, Christchurch, New Zealand
Royds, Janice A; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Slatter, Tania L; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Robinson, Bridget A; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand ; Canterbury Regional Cancer and Haematology Service, Canterbury District Health Board, Christchurch, New Zealand ; Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
Phillips, Elisabeth; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
Dachs, Gabi U; Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand. gabi.dachs@otago.ac.nz
Language :
English
Title :
Ascorbate content of clinical glioma tissues is related to tumour grade and to global levels of 5-hydroxymethyl cytosine.
CMRF - Canterbury Medical Research Foundation University of Otago. Division of Health Sciences Mackenzie Charitable Foundation
Funding text :
Funding was obtained from the Canterbury Medical Research Foundation, the University of Otago Research Grants and the Mackenzie Charitable Foundation.We are grateful to the patients with brain cancer who gifted their tumours to research. We also thank He Taonga Tapu Cancer Society Tissue Bank for collecting and processing of samples, Dr Juliet Pullar for help with ascorbate analysis, biostatistician Associate Professor John Pearson (University of Otago, Christchurch) for statistical advice, and the University of Otago for EB’s doctoral scholarship.
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