title: Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine.
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.
authors: Van Andel Research Institute, Grand Rapids, MI 49503;
authors: Minmin
authors: M
authors: Liu
authors: Van Andel Research Institute, Grand Rapids, MI 49503;
authors: Hitoshi
authors: H
authors: Ohtani
authors: Van Andel Research Institute, Grand Rapids, MI 49503;
authors: Wanding
authors: W
authors: Zhou
authors: Department of Hematology, Rigshospitalet, 2100 Copenhagen Ø, Denmark;
authors: Andreas Due
authors: AD
authors: Ørskov
authors: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089;
authors: Jessica
authors: J
authors: Charlet
authors: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287.
authors: Yang W
authors: YW
authors: Zhang
authors: Van Andel Research Institute, Grand Rapids, MI 49503;
authors: Hui
authors: H
authors: Shen
authors: Van Andel Research Institute, Grand Rapids, MI 49503; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287.
authors: Stephen B
authors: SB
authors: Baylin
authors: Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089; peter.jones@vai.org gliang@usc.edu kirsten.groenbaek@regionh.dk.
authors: Gangning
authors: G
authors: Liang
authors: Department of Hematology, Rigshospitalet, 2100 Copenhagen Ø, Denmark; peter.jones@vai.org gliang@usc.edu kirsten.groenbaek@regionh.dk.
authors: Kirsten
authors: K
authors: Grønbæk
authors: Van Andel Research Institute, Grand Rapids, MI 49503; peter.jones@vai.org gliang@usc.edu kirsten.groenbaek@regionh.dk.
authors: Peter A
authors: PA
authors: Jones
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001206:Ascorbic Acid Deficiency / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D000077209:Decitabine; D049308:Dioxygenases; D004357:Drug Synergism; D020077:Endogenous Retroviruses / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D019337:Hematologic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007372:Interferons / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012330:RNA, Double-Stranded / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D012330:RNA, Double-Stranded; D000077209:Decitabine; D007372:Interferons; D049308:Dioxygenases; C541081:TET2 protein, human; D008780:Methyltransferases; D001374:Azacitidine; D001205:Ascorbic Acid
keywords: 5-hydroxymethylcytosine; DNA methyltransferase inhibitor; endogenous retrovirus; epigenetic therapy; vitamin C