期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 37, 页码 10238-10244出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612262113
关键词
epigenetic therapy; DNA methyltransferase inhibitor; vitamin C; endogenous retrovirus; 5-hydroxymethylcytosine
资金
- National Cancer Institute [R01CA082422]
- VARI through the VARI-Stand Up To Cancer Epigenetics Dream Team (Stand Up To Cancer is a program of the Entertainment Industry Foundation)
- Vicky Joseph Cancer Research Fund
- Novo Nordisk Foundation
- Danish Cancer Society
- Lundbeck Foundation
- Lundbeck Foundation [R180-2014-3675] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0003435] Funding Source: researchfish
- Novo Nordisk Foundation Section for Basic Stem Cell Biology [Grønbæk group NNF] Funding Source: researchfish
- The Danish Cancer Society [R124-A7695] Funding Source: researchfish
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.
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