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A Key Role of DNA Damage-Inducible Transcript 4 (DDIT4) Connects Autophagy and GLUT3-Mediated Stemness To Desensitize Temozolomide Efficacy in Glioblastomas.

ABSTRACT: DNA damage-inducible transcript 4 (DDIT4) is known to participate in various cancers, including glioblastoma multiforme (GBM). However, contradictory roles of DDIT4 exist in inducing cell death and possessing anti-apoptotic functions against cancer progression. Herein, we investigated DDIT4 signaling in GBM and temozolomide (TMZ) drug resistance. We identified that TMZ induced DDIT4 upregulation, leading to desensitization against TMZ cytotoxicity in GBM cells. Higher DDIT4 levels were found in glioma cells and mesenchymal-type GBM patients, and these higher levels were positively correlated with mesenchymal markers. Furthermore, patients with lower DDIT4 levels, especially O-6-methylguanine-DNA methyltransferase (MGMT)-methylated patients, exhibited better TMZ therapeutic efficacy. We determined that higher levels of 5 DDIT4-associated downstream genes, including SLC2A3 (also known as glucose transporter 3 (GLUT3)), can be used to predict a poor prognosis. Among these 5 genes, only GLUT3 was upregulated in both TMZ-treated and DDIT4-overexpressing cells. DDIT4-mediated GLUT3 expression was also identified, and its expression decreased TMZ's cytotoxicity. A significant correlation existed between DDIT4 and GLUT3. DDIT4 signaling was found to be involved in both glycolytic and autophagic pathways. However, GLUT3 only participated in the exhibition of DDIT4-mediated stemness, resulting from glycolytic regulation, but not in DDIT4-mediated autophagic signaling. Finally, we identified TMZ-upregulated activating transcription factor 4 (ATF4) as an upstream regulator of DDIT4-mediated GLUT3/stemness signaling and autophagy. Consequently, ATF4/DDIT4 signaling was connected to both autophagy and GLUT3-regulated stemness, which are involved in TMZ drug resistance and the poor prognoses of GBM patients. Targeting DDIT4/GLUT3 signaling might be a new direction for glioma therapy.

SUBMITTER: Ho KH

PROVIDER: S-EPMC7609792 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo identify novel epigenetic signatures that could provide predictive information that is complementary to promoter methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) gene for predicting temozolomide (TMZ) response, among glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP) METHODS: Different cohorts of primary non-G-CIMP GBMs with genome-wide DNA methylation microarray data were included for discovery and validation of a multimarker signature, combined using a RISK score model. Different statistical analyses and functional experiments were performed for clinical and biological validation.ResultsBy employing discovery cohorts with radiotherapy (RT) and TMZ versus RT alone and a strict multistep selection strategy, we identified seven CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs with RT/TMZ, independent of age, MGMT promoter methylation status, and other identified CpGs. A RISK score signature of the 7 CpGs was developed and validated to distinguish non-G-CIMP GBMs with differential survival outcomes to RT/TMZ, but not to RT alone. The interaction analyses also showed differential outcomes to RT/TMZ versus RT alone within the RISK score-based subgroups. The signature could also improve the risk classification by age and MGMT promoter methylation status. Functional experiments showed that HSBP2 appeared to be epigenetically regulated by one identified CpG and was associated with TMZ resistance, but it was not associated with cell proliferation or apoptosis in GBM cell lines. The predictive value of the single CpG methylation of HSBP2 by pyrosequencing was observed in a local cohort of isocitrate dehydrogenase 1 (IDH1) R132H wild-type GBMs.ConclusionsThis novel epigenetic signature might be a promising predictive (but not a general prognostic) biomarker and be helpful for refining the MGMT-based guiding approach to TMZ usage in non-G-CIMP GBMs.

Project description:Temozolomide (TMZ) is considered a standard chemotherapeutic agent for glioblastoma (GBM). Characterizing the biological molecules and signaling pathways involved in TMZ sensitivity would be helpful for selecting therapeutic schemes and evaluating prognosis for GBM. Thus, in the present study, we selected 34 glioma cell lines paired with specific IC50 values of TMZ obtained from CancerRxGene and RNA-seq data downloaded from the Cancer Cell Line Encyclopedia to identify genes related to TMZ sensitivity. The results showed that 1,373 genes were related to the response of GBM cells to TMZ. Biological function analysis indicated that epithelial-mesenchymal transition, Wnt signaling, and immune response were the most significantly activated functions in TMZ-resistant cell lines. Additionally, negative regulation of telomere maintenance via telomerase was enriched in TMZ-sensitive glioma cell lines. We also preliminarily observed a synergistic effect of combination treatment comprising TMZ and a telomerase inhibitor in vitro. We identified six genes (MROH8, BET1, PTPRN2, STC1, NKX3-1, and ARMC10) using the random survival forests variable hunting algorithm based on the minimum error rate of the gene combination and constructed a gene expression signature. The signature was strongly related to GBM clinical characteristics and exhibited good prognosis accuracy for both The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Patients in the high score group had a shorter survival time than those in the low score group (11.2 vs. 22.2 months, hazard ratio = 7.31, p = 4.59e-11) of the TCGA dataset. The CGGA dataset was selected as a validation group with 40 patients in the high score set and 43 patients in the low score set (12.5 vs. 28.8 months, hazard ratio = 3.42, p = 8.61e-5). Moreover, the signature showed a better prognostic value than MGMT promoter methylation in both datasets. We also developed a nomogram for clinical use that integrated the TMZ response signature and four other risk factors to individually predict patient survival after TMZ chemotherapy. Overall, our study provides promising therapeutic targets and potential guidance for adjuvant therapy of GBM.

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A Key Role of DNA Damage-Inducible Transcript 4 (DDIT4) Connects Autophagy and GLUT3-Mediated Stemness To Desensitize Temozolomide Efficacy in Glioblastomas.

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