Methylation dependent down-regulation of G0S2 leads to suppression of invasion and improved prognosis of IDH1-mutant glioma

Abstract

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.

Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response

“…By analyzing The Cancer Genome Atlas (TCGA), Fukunaga et al showed that pateients in the higher G0S2 expression group had a poorer prognosis [18]. They also demonstrated that G0S2 expression levels were higher in recurrent tumor specimens that that at the initial diagnosis in the same patients [18]. Here in this study, we show that G0S2 promotes tumor growth in gliomas.…”

“…Although Zagani et al [43] demonstrated that Eμ-Myc transgenic mouse model was not the correct model to conduct studies on G0S2, they found deletion of the G0S2 gene in mice did not show any effect on the latency of cancer progression in the Eμ-Myc model of lymphoma [43]. By analyzing The Cancer Genome Atlas (TCGA), Fukunaga et al showed that pateients in the higher G0S2 expression group had a poorer prognosis [18]. They also demonstrated that G0S2 expression levels were higher in recurrent tumor specimens that that at the initial diagnosis in the same patients [18].…”

“…G0S2 is demonstrated to function as a lipolytic inhibitor in lipid metabolism to regulate lipid droplet turnover [12], and lipid droplets were identified as a signature of GBM and inversely correlated with GBM patient survival [14]. Acumulated data have indicated that G0S2 is also involved in cancer [10, 15–17], including glioma [18]. However, the function of G0S2 in cancers is still largely unknown.…”

Genetic Programs Driving Oncogenic Transformation: Lessons from In Vitro Models

“…This influence could be relevant for the metabolic adaptation of cancer cells. However, preliminary studies have provided conflicting data on a role of G0S2 in cancer cells [34,[52][53][54]. Our discovery about the existence of strong correlations between G0S2 levels and patients' survival in different cancers suggests the needing of a more extensive investigation about the impact of this gene on the metabolism and proliferation of transformed cells.…”

Non-canonical roles for metabolic enzymes and intermediates in malignant progression and metastasis

“…IDH mutations that produce 2-hydroxyglutarate can cause EMT in colorectal cancer cells through driving the expression of the transcription factor ZEB1 [89,91]. Conversely, IDH mutant gliomas can have better prognosis due to promotion of methylation and thereby suppression of invasion-promoting genes such as G0S2 [92].…”