Department of Neurosurgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
Department of Molecular Neuroscience, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
PLoS One. 2018 Nov 2;13(11):e0206552. doi: 10.1371/journal.pone.0206552. eCollection 2018.
Isocitrate dehydrogenase (IDH) mutations are a prognostic factor in diffuse glioma. However, the mechanism by which these mutations improve prognosis are not clear. In a subset of IDH-mutant glioma, remodeling of the methylome results in the glioma-CpG island methylator phenotype (G-CIMP) and transcriptional reorganization. In this study, we focus on G0/G1 switch 2 (G0S2), which is highly downregulated in G-CIMP glioma. We found that G0S2 expression tended to increase as the WHO grade increased, and G0S2 knockdown inhibited glioma invasion. Additionally, we revealed that the overexpression of the DNA demethylase Ten-eleven translocation 2 (TET2) in IDH1-plasmid transfected glioblastoma multiforme (GBM) cells restored G0S2 expression. These results indicate that G0S2 is epigenetically silenced in IDH1-mutant glioma. In addition, the stereotactic delivery of glioma cells with decreased G0S2 expression in the mouse brain resulted in prolonged survival. The Cancer Genome Atlas (TCGA) analysis also indicated that survival is longer in the lower G0S2 expression group than in the higher G0S2 expression group. Moreover, G0S2 expression was higher in recurrent tumor specimens than at the initial diagnosis in the same patient. These results provide one explanation for the improved survival in IDH1-mutant glioma as well as a new epigenetic target for glioma treatment.
异柠檬酸脱氢酶（IDH）突变是弥漫性神经胶质瘤的预后因素。然而，这些突变改善预后的机制尚不清楚。在一组 IDH 突变型神经胶质瘤中，甲基组的重塑导致神经胶质瘤-CpG 岛甲基化表型（G-CIMP）和转录重排。在本研究中，我们关注 G0/G1 开关 2（G0S2），其在 G-CIMP 神经胶质瘤中高度下调。我们发现，G0S2 的表达随着 WHO 分级的增加而趋于增加，G0S2 敲低抑制神经胶质瘤侵袭。此外，我们揭示了在 IDH1 质粒转染的多形性胶质母细胞瘤（GBM）细胞中过表达 DNA 去甲基化酶 Ten-eleven 易位 2（TET2）可恢复 G0S2 的表达。这些结果表明 G0S2 在 IDH1 突变型神经胶质瘤中被表观遗传沉默。此外，在小鼠大脑中降低 G0S2 表达的神经胶质瘤细胞的立体定向递送导致存活时间延长。癌症基因组图谱（TCGA）分析还表明，低表达 G0S2 组的生存时间长于高表达 G0S2 组。此外，在同一患者的复发性肿瘤标本中，G0S2 的表达高于初始诊断时。这些结果为 IDH1 突变型神经胶质瘤的生存改善提供了一种解释，并为神经胶质瘤治疗提供了一个新的表观遗传靶点。
