Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine
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Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine. / Liu, Minmin; Ohtani, Hitoshi; Zhou, Wanding; Ørskov, Andreas Due; Charlet, Jessica; Zhang, Yang W; Shen, Hui-Rong; Baylin, Stephen B; Liang, Gangning; Grønbæk, Kirsten; Jones, Peter A.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 37, 10238-44, 13.09.2016.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Vitamin C increases viral mimicry induced by 5-aza-2'-deoxycytidine
AU - Liu, Minmin
AU - Ohtani, Hitoshi
AU - Zhou, Wanding
AU - Ørskov, Andreas Due
AU - Charlet, Jessica
AU - Zhang, Yang W
AU - Shen, Hui-Rong
AU - Baylin, Stephen B
AU - Liang, Gangning
AU - Grønbæk, Kirsten
AU - Jones, Peter A
PY - 2016/9/13
Y1 - 2016/9/13
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1073/pnas.1612262113
DO - 10.1073/pnas.1612262113
M3 - Journal article
C2 - 27573823
VL - 113
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 37
M1 - 10238-44
ER -
ID: 179169175