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Contributed by Peter A. Jones, July 26, 2016 (sent for review June 22, 2016; reviewed by Lucy A. Godley and Adam R. Karpf)
Significance
Our work shows a remarkable synergy between physiological levels of vitamin C and 5-aza-CdR. The combination enhances the viral mimicry response to DNA methyltransferase inhibitors, including the upregulation of endogenous retroviruses in the dsRNA form and the induction of viral defense pathways. Because patients with hematological and other cancers are often markedly vitamin C deficient, the addition of vitamin C to treatment protocols may be a straightforward way to increase the clinical efficacy of such drugs in patients with myelodysplastic syndrome and leukemia.
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 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.
- epigenetic therapy
- DNA methyltransferase inhibitor
- vitamin C
- endogenous retrovirus
- 5-hydroxymethylcytosine
Footnotes
↵1M.L., H.O., W.Z., and A.D.Ø. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: peter.jones{at}vai.org, gliang{at}usc.edu, or kirsten.groenbaek{at}regionh.dk.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016.
Author contributions: M.L., G.L., and P.A.J. designed research; M.L., H.O., A.D.Ø., J.C., and K.G. performed research; Y.W.Z. and S.B.B. contributed new reagents/analytic tools; M.L., H.O., W.Z., A.D.Ø., H.S., and K.G. analyzed data; and M.L. and P.A.J. wrote the paper.
Reviewers: L.A.G., University of Chicago; and A.R.K., University of Nebraska Medical Center.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited at the Gene Expression Omnibus (GEO), www.ncbi.nlm.nih.gov/geo/ (accession codes GSE77031, GSE77032, GSE77034, GSE77035, and GSE77036).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612262113/-/DCSupplemental.
Freely available online through the PNAS open access option.
Vitamin C increases viral mimicry induced by DNMTi
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