Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine

Minmin Liu, Hitoshi Ohtani, Wanding Zhou, Andreas Due Ørskov, Jessica Charlet, Yang W. Zhang, Hui Shen, Stephen B. Baylin, Gangning Liang, Kirsten Grønbæk, Peter A. Jones

Research output: Contribution to journalArticlepeer-review

Abstract

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 IFNinducing 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.

Original languageEnglish (US)
Pages (from-to)10238-10244
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number37
DOIs
StatePublished - Sep 13 2016

Keywords

  • 5-hydroxymethylcytosine
  • DNA methyltransferase inhibitor
  • Endogenous retrovirus
  • Epigenetic therapy
  • Vitamin C

ASJC Scopus subject areas

  • General

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