Folate Supplementation Limits the Aggressiveness of Glioma via the Remethylation of DNA Repeats Element and Genes Governing Apoptosis and Proliferation
Folate Supplementation Limits the Aggressiveness of Glioma via the Remethylation of DNA Repeats Element and Genes Governing Apoptosis and Proliferation
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DOI：
10.1158/1078-0432.ccr-08-2062
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Cartron, Pierre-Francois
中科院分区：
文献类型：
--
作者：
Hervouet, Eric;Debien, Emilie;Cartron, Pierre-Francois
目的：我们研究了叶酸补充剂是否可以通过DNA再甲基化来限制胶质瘤的侵袭性，因为(a)癌症基因组的特征是低水平的DNA甲基化（或5-甲基胞嘧啶，5mc）；(b)叶酸是DNA甲基化酶催化的DNA甲基化反应中的甲基供体分子s -腺苷-蛋氨酸的主要产生物。实验设计：分析叶酸补充对胶质瘤细胞整体DNA甲基化状态、DNA重复元件甲基化状态、替莫唑胺诱导细胞凋亡敏感性及增殖指数的影响。最后，我们分析了DNA甲基化水平是否可以作为预后因素和/或生物标志物，在使用叶酸补充作为辅助的抗胶质瘤治疗中。结果：我们的数据显示，胶质瘤的形成伴随着5mc水平的降低，而这种低水平的5mc是多形性胶质母细胞瘤患者预后不良的因素。我们还发现，叶酸的补充通过Spl/ sp3介导的Dnmt3a和Dnmt3b蛋白编码基因的转录上调来增强DNA的再甲基化，Dnmt3a和Dnmt3b蛋白是两种新的甲基转移酶。最后，我们发现叶酸诱导的DNA甲基化限制了胶质瘤细胞的增殖，并通过与这些过程相关的基因（PDGF-B、MGMT、survivin和bcl-w）的甲基化，增加了对替莫唑胺诱导的胶质瘤细胞凋亡的敏感性。结论：本研究表明，叶酸补充剂可能是临床前和/或临床研究中抗胶质瘤治疗设计的一种有希望的辅助剂。
Purpose: We have investigated whether the folate supplementation could be used to limit the aggressiveness of glioma through the DNA remethylation because (a) the cancer genome is characterized by a low level of DNA methylation (or 5-methylcytosine, 5 mC); and (b) folate is the main generator of S-adenosyl-methionine, the methyl donor molecule in the DNA methylation reaction catalyzed by the DNA methyltranferases.Experimental Design: The effects of folate supplementations were analyzed on the global DNA methylation status, the methylation status of DNA repeat element, the sensitivity of temozolomide-induced apoptosis, and the proliferation index of glioma cells. Finally, we analyzed whether the DNA methylation level could be used as a prognostic factor and/or a biomarker in an antiglioma therapy using folate supplementation as an adjuvant.Results: Our data show that gliomagenesis is accompanied by a reduction in 5 mC levels and that this low level of 5 mC is a poor prognostic factor in Glioblastoma Multiforme patients. We also show that folate supplementation enhanced the DNA remethylation through the Spl/Sp3-mediated transcriptional up-regulation of genes coding for Dnmt3a and Dnmt3b proteins, two de novo methyltranferases. Finally, we show that the folate-induced DNA methylation limits proliferation and increases the sensitivity to temozolomide-induced apoptosis in glioma cells through methylation of the genes implicated in these processes (PDGF-B, MGMT, survivin, and bcl-w).Conclusion: This study suggests that folate supplementation could be a promising adjuvant for the future design of antiglioma therapies in preclinical and/or clinical studies.