Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine
| Autor: | Wanding Zhou, Minmin Liu, Kirsten Grønbæk, Yang W. Zhang, Andreas Due Ørskov, Peter A. Jones, Stephen B. Baylin, Hui-Rong Shen, Gangning Liang, Hitoshi Ohtani, Jessica Charlet |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Methyltransferase viruses DNA Methyltransferase Inhibitor Apoptosis Ascorbic Acid Biology Decitabine Dioxygenases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Proto-Oncogene Proteins Humans Enzyme Inhibitors Cell Proliferation RNA Double-Stranded 5-Hydroxymethylcytosine Multidisciplinary Vitamin C Endogenous Retroviruses Drug Synergism Methyltransferases DNA Methylation Biological Sciences Ascorbic acid Molecular biology DNA-Binding Proteins 030104 developmental biology DNA demethylation chemistry Hematologic Neoplasms 030220 oncology & carcinogenesis Ascorbic Acid Deficiency Azacitidine Female Interferons Epigenetic therapy |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:10238-10244 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1612262113 |
| Popis: | Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin C deficiency in patients with hematological and other cancers may improve responses to epigenetic therapy with DNMTis. |
| Databáze: | OpenAIRE |
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