Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma
Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma
复制标题
野生型 IDH1 和突变型 IDH1 反向调节胶质瘤中的 Planoplanin 表达
DOI：
10.1016/j.tranon.2020.100758
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发表时间：
2020-04-01
影响因子：
5
通讯作者：
Ye, Jing
中科院分区：
文献类型：
--
作者：
Sun, Chao;Xiao, Liming;Ye, Jing
异柠檬酸脱氢酶（IDH）突变经常发生在低级别胶质瘤中，导致全基因组表观遗传学改变。野生型IDH 1被报道参与脂质生物合成和氨基酸代谢，但其在肿瘤发生中的作用仍不清楚。本研究检测IDH突变型和野生型胶质瘤中IDH 1和Podoplanin（Pdpn）的表达，并进一步分析其在胶质瘤中的相关性。此外，通过荧光素酶测定和启动子甲基化分析研究野生型IDH 1和突变型IDH 1对Pdpn表达的调节。我们的研究表明，Pdpn在IDH突变的胶质瘤中几乎检测不到，但在更高级别的IDH野生型胶质瘤中强烈表达。Pdpn过表达促进胶质瘤细胞的迁移，但对细胞生长影响不大。此外，Pdpn表达与野生型IDH-野生型胶质瘤中野生型IDH 1水平的增加呈正相关。结论：野生型IDH 1显著促进胶质瘤细胞Pdpn的转录和表达，而突变型IDH 1和D-2-hydroxyglutarate显著抑制胶质瘤细胞Pdpn的表达。此外，我们的研究结果显示，在胶质瘤中，野生型和突变型IDH 1对Pdpn启动子CpG岛甲基化的调控作用相反。总之，我们的研究结果表明野生型和突变型IDH 1通过调控其启动子甲基化反向调控胶质瘤中Pdpn的表达，这为理解野生型和突变型IDH 1在表观遗传调控和肿瘤发生中的关系提供了基础。
Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations. The wild-type IDH1 is reported to participate in lipid biosynthesis and amino acid metabolism, but its role in tumorigenesis is still unclear. In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed. In addition, the regulation of wild-type IDH1 and mutant IDH1 on Pdpn expression was investigated by luciferase assays and promoter methylation analysis. Our study showed that Pdpn was almost undetectable in IDH-mutated glioma but strongly expressed in higher-grade IDH-wild-type glioma. Pdpn overexpression promoted the migration of glioma cells but had little effect on cell growth. Moreover, Pdpn expression was positively correlated with the increased wild-type IDH1 levels in IDH-wild-type glioma. Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells. Besides, our results revealed that the methylation of CpG islands in the Pdpn promoter was opposingly regulated by wild-type and mutant IDH1 in glioma. Collectively, our results indicated that wild-type and mutant IDH1 opposingly controlled the Pdpn expression in glioma by regulating its promoter methylation, which provides a basis for understanding the relationship between wild-type and mutant IDH1 in epigenetic regulation and tumorigenesis.