Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine
Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine
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DOI：
10.1073/pnas.1612262113
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发表时间：
2016-09-13
影响因子：
11.1
通讯作者：
Jones, Peter A.
中科院分区：
文献类型：
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作者：
Liu, Minmin;Ohtani, Hitoshi;Jones, Peter A.
维生素C缺乏在癌症患者中发现，可能使各种治疗模式复杂化。在这里，我们展示了这种缺陷如何影响DNA甲基转移酶抑制剂（DNMTis）用于治疗血液肿瘤。在体外，当将生理水平的维生素C添加到低剂量的DNMTi 5-氮杂-2 '-脱氧胞苷（5-氮杂-CdR）中时，会协同抑制癌细胞增殖并增加细胞凋亡。这些作用与增强的免疫信号相关，包括双向转录的内源性逆转录病毒（ERV）转录物的表达增加、胞质dsRNA增加和IFN诱导细胞应答的激活。这种协同效应可能是DNMTi的被动DNA去甲基化和ERV的LTR区域的10 - 11易位（泰特）酶将5-甲基胞嘧啶（5 mC）主动转化为5-羟甲基胞嘧啶（5 hmC）的结果，因为维生素C充当泰特蛋白的辅因子。此外，TET 2敲除降低了两种化合物之间的协同作用。此外，我们发现许多血液肿瘤患者明显缺乏维生素C。因此，我们的数据表明，纠正血液病和其他癌症患者的维生素C缺乏症可能会改善DNMTis表观遗传治疗的反应。
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.