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Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma.
Translational Oncology ( IF 4.5 ) Pub Date : 2020-03-21 , DOI: 10.1016/j.tranon.2020.100758
Chao Sun 1 , Liming Xiao 2 , Yuanlin Zhao 2 , Jiankuan Shi 3 , Yuan Yuan 2 , Yu Gu 2 , Feng Zhang 2 , Xing Gao 2 , Ying Yang 2 , Risheng Yang 2 , Junhui Qin 2 , Jin Zhang 2 , Chao Wang 4 , Yingmei Wang 2 , Zhe Wang 2 , Peizhen Hu 2 , Ting Chang 5 , Liang Wang 6 , Gang Wang 7 , Huangtao Chen 8 , Zhuyi Li 5 , Jing Ye 1
Affiliation  

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.



中文翻译:

野生型IDH1和突变IDH1相反地调节胶质瘤中Podoplanin的表达。

在低级神经胶质瘤中经常发生异柠檬酸脱氢酶(IDH)突变,这导致全基因组表观遗传学改变。据报道,野生型IDH1参与脂质的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。在这项研究中,确定IDH1和podoplanin(Pdpn)在IDH突变和IDH野生型神经胶质瘤中的表达,并进一步分析它们在神经胶质瘤中的关系。此外,通过荧光素酶测定和启动子甲基化分析研究了野生型IDH1和突变IDH1对Pdpn表达的调控。我们的研究表明,Pdpn在IDH突变的神经胶质瘤中几乎无法检测到,但在较高级别的IDH野生型神经胶质瘤中却强烈表达。Pdpn的过表达促进神经胶质瘤细胞的迁移,但对细胞生长的影响很小。此外,Pdpn表达与IDH野生型神经胶质瘤中野生型IDH1水平升高呈正相关。一致地,野生型IDH1极大地促进了Pdpn的转录和表达,但突变体IDH1和D-2-羟基戊二酸显着抑制了胶质瘤细胞中Pdpn的表达。此外,我们的结果表明,CpG岛的甲基化在神经胶质瘤中,Pdpn启动子受到野生型和突变IDH1的反向调控。总体而言,我们的结果表明野生型和突变IDH1通过调节其启动子甲基化来相反地控制神经胶质瘤中Pdpn的表达,这为理解野生型和突变IDH1在表观遗传调控和肿瘤发生中的关系提供了基础。

更新日期:2020-03-21
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