Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response

Abstract

Background Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM. Methods Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan–Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining. Results Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance. Conclusions Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas. Electronic supplementary material The online version of this article (10.1186/s13046-019-1151-x) contains supplementary material, which is available to authorized users.

Different Mechanisms Underlie the Metabolic Response of GBM Stem-Like Cells to Ionizing Radiation: Biological and MRS Studies on Effects of Photons and Carbon Ions

“…In contrast, in line #83, MLs are segregated and stored mainly in cytoplasmic lipid droplets where they are protected from oxidation and from the formation of unstable lipid peroxides, which are toxic to cells [ 53 ]. It has been recently reported [ 54 ] that lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2.…”

Low G0S2 gene expression levels in peripheral blood may be a genetic marker of acute myocardial infarction in patients with stable coronary atherosclerotic disease

“…[ 17 ] It has been shown to play a variety of important roles in cellular function in both humans and mice, such as cell proliferation, apoptosis, and oxidative phosphorylation. [ 18 ] Over expression of G0S2 in the liver results in the increased accumulation of triglycerides and promotes the formation of fatty liver. [ 24 , 25 ] In fat cells, the G0S2 gene expression product can directly bind to ATGL and reduce ATGL-mediated lipolysis by inhibiting the activity of its triacylglycerol hydrolase.…”

“…For example, low expression of the G0S2 gene inhibits the occurrence of glioma in vivo. [ 18 ] However, in breast cancer, especially in patients that are estrogen receptor-positive (ER+), low G0S2 gene expression is associated with an increased rate of recurrence. [ 31 ] In addition, DNA methylation of the G0S2 gene may be an important biomarker for squamous cell lung cancer.…”

“…[ 16 ] Later studies have shown that its expression is closely related to lipolysis, [ 17 ] cell proliferation, apoptosis, and oxidative phosphorylation mediated by fatty triglyceride lipase (ATGL). [ 18 ] As a result, we aimed to increase the sample size of patients compared to those studies to verify whether the expression of the GOS2 gene is down-regulated in AMI patients from a larger population through clinically available peripheral blood samples.…”

Correction to: Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response

“…In the original publication of this article [1], the Gene Expression Omnibus (GEO) accession code GSE79772 is wrong. The correct accession code should be GSE86213.…”