Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines

Zhang, Yulin; Kong, Yahui; Ma, Yuan; Ni, Shilei; Wikerholmen, T; Xi, Kaiyan; Zhao, Feihu; Zhao, Zhimin; Wang, Junpeng; Huang, Bin; Chen, Anjing; Yao, Zhong; Han, Mingzhi; Feng, Zichao; Hu, Yaotian; Thorsen, Frits; Wang, Jiang; Li, Xingang

doi:10.1038/s41388-020-01622-3

Cited by 115 publications

(87 citation statements)

References 50 publications

(34 reference statements)

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“…Liu et al also identified NCOA4 as a prognostic factor in glioma (60). COPZ1 knockdown increased the expression level of NCOA4, which elevated iron levels and reactive oxygen species, resulting ferroptosis and reduced growth of GBM cells (61). Moreover, Pinton et al reported that NCOA4 is overexpressed in bone marrowderived macrophages from glioma lesions (62).…”

Section: Discussionmentioning

confidence: 99%

Identification of Iron Metabolism-Related Genes as Prognostic Indicators for Lower-Grade Glioma

Wang

et al. 2021

Front. Oncol.

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Lower-grade glioma (LGG) is characterized by genetic and transcriptional heterogeneity, and a dismal prognosis. Iron metabolism is considered central for glioma tumorigenesis, tumor progression and tumor microenvironment, although key iron metabolism-related genes are unclear. Here we developed and validated an iron metabolism-related gene signature LGG prognosis. RNA-sequence and clinicopathological data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were downloaded. Prognostic iron metabolism-related genes were screened and used to construct a risk-score model via differential gene expression analysis, univariate Cox analysis, and the Least Absolute Shrinkage and Selection Operator (LASSO)-regression algorithm. All LGG patients were stratified into high- and low-risk groups, based on the risk score. The prognostic significance of the risk-score model in the TCGA and CGGA cohorts was evaluated with Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) curve analysis. Risk- score distributions in subgroups were stratified by age, gender, the World Health Organization (WHO) grade, isocitrate dehydrogenase 1 (IDH1) mutation status, the O6‐methylguanine‐DNA methyl‐transferase (MGMT) promoter-methylation status, and the 1p/19q co-deletion status. Furthermore, a nomogram model with a risk score was developed, and its predictive performance was validated with the TCGA and CGGA cohorts. Additionally, the gene set enrichment analysis (GSEA) identified signaling pathways and pathological processes enriched in the high-risk group. Finally, immune infiltration and immune checkpoint analysis were utilized to investigate the tumor microenvironment characteristics related to the risk score. We identified a prognostic 15-gene iron metabolism-related signature and constructed a risk-score model. High risk scores were associated with an age of > 40, wild-type IDH1, a WHO grade of III, an unmethylated MGMT promoter, and 1p/19q non-codeletion. ROC analysis indicated that the risk-score model accurately predicted 1-, 3-, and 5-year overall survival rates of LGG patients in the both TCGA and CGGA cohorts. KM analysis showed that the high-risk group had a much lower overall survival than the low-risk group (P < 0.0001). The nomogram model showed a strong ability to predict the overall survival of LGG patients in the TCGA and CGGA cohorts. GSEA analysis indicated that inflammatory responses, tumor-associated pathways, and pathological processes were enriched in high-risk group. Moreover, a high risk score correlated with the infiltration immune cells (dendritic cells, macrophages, CD4+ T cells, and B cells) and expression of immune checkpoint (PD1, PDL1, TIM3, and CD48). Our prognostic model was based on iron metabolism-related genes in LGG, can potentially aid in LGG prognosis, and provides potential targets against gliomas.

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Section: Discussionmentioning

confidence: 99%

Identification of Iron Metabolism-Related Genes as Prognostic Indicators for Lower-Grade Glioma

Wang

et al. 2021

Front. Oncol.

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“… 15 , 18 Studies have reported that SIRT3/AMPK/mTOR/GPx4 and COPZ1/NCOA4/FTH1-related pathways modulate autophagy-dependent ferroptosis cancer cell death. 19 , 20 The studies confirmed that the increase of SIRT3 expression could stimulate AMPK mTOR to release iron from ferritin, which leads to free iron accumulation and lipid peroxidation, thereby promoting autophagy activation. The decrease of SIRT3 can inhibit ferroptosis through regulating the GPx4 level.…”

Section: Introductionmentioning

confidence: 81%

Autophagy-Dependent Ferroptosis-Related Signature is Closely Associated with the Prognosis and Tumor Immune Escape of Patients with Glioma

Sun¹,

Yan²,

Ma³

et al. 2022

IJGM

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Background:Ferroptosis is an autophagy-dependent form of cell death, sometimes called "ferritinophagy". Its related pathway has been proven to regulate the programmed death of glioma stem cells. Mining autophagy-dependent ferroptosis-related gene (AD-FRG) signature could facilitate the discovery of mechanisms and therapeutic targets showing drug resistance to chemotherapeutic drugs. Methods: We exhaustively searched HADB, MSigDB and FerrDb datasets and obtained 25 genes confirmed to exist in autophagy and ferroptosis death pathways. Glioma gene expression and clinicopathological data were collected from TCGA and CGGA datasets. Results: Lasso regression and Cox regression analysis were carried out to construct a nine AD-FRGs signature (SIRT1, MTDH, HSPB1, CISD2, HMOX1, ATG7, MTOR, PRKAA2 and EIF2AK4). ROC curve showed that nine genes signature could effectively predict 1-(AUC = 0.869), 3-(AUC = 0.922) and 5-year (AUC = 0.870) survival rates. Immunohistochemical images confirmed the protein expression level of the gene model. The prognostic nomogram of risk score, age, WHO grade, isocitrate dehydrogenase (IDH) wild-type condition, 1p/19q co-deletion state was built. The calibration curve demonstrated that the prediction of the nomogram is highly consistent with the actual results. Moreover, tumor microenvironment analysis showed that the high-risk group was associated with high immune infiltration status and high tumor purity. Correlation analysis showed that the expression of SIRT1, CISD2 and HSPB1 might be related to macrophage infiltration and immunotolerance in glioma tissues. Conclusion: Based on autophagy-dependent ferroptosis-related genes, we established gene signature and nomogram that maybe effectively predict the overall survival rate of glioma and correlate with the immunosuppressive tumor microenvironment (TME).

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“…Despite breakthroughs in basic glioma research over the past decades, the median patient survival is less than 15 months [13][14][15] . The development of chemotherapeutic drugs for glioma has been slow, mainly due to the lack of ability of most drugs to be delivered across the blood-brain barrier and the fact that increasing drug doses can have signi cant side effects on patients' somatic functions, while the application of chemotherapeutic drugs can also enhance drug resistance in glioma 2,16,17 . Therefore, exploring the mechanisms related to the biological behavior of glioma cells and nding new targets for glioma therapy are expected to provide new directions for the treatment of glioma.…”

Section: Discussionmentioning

confidence: 99%

“…Glioma is the most commonly diagnosed primary malignant brain tumor in adults, and 70% of them are high-grade gliomas (glioblastoma, GBM) 1 . In the clinical treatment of GBM, the median survival of patients is only 14 months despite the proven effectiveness of surgery combined with radiotherapy and chemotherpy 2 . Compared with other tumors, GBM is more sophisticated in treatment due to its high heterogeneity and high recurrence rate 3 .…”

Section: Introductionmentioning

confidence: 99%

Loss of TXNDC12 Induces Oxidative Stress-mediated Autophagy in Glioblastoma Cell Lines

Zhang¹,

Bao²,

Li³

et al. 2021

Preprint

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Redox homeostasis in glioblastoma cells is very important, but how it is maintained is still not well understood. Herein, we identified thioredoxin domain-containing protein 12 (TXNDC12) as a therapeutic target candidate which significantly maintained redox homeostasis in GBM cells. Overexpression of TXNDC12 was associated with increased tumor grade and poor prognosis in patients with glioma (P < 0.001), according to the analysis of expression data from the public database Cancer Genome Atlas. TXNDC12 protein levels were significantly elevated in glioblastoma compared to non-tumor brain tissue samples by immunohistochemistry and western blot analysis. Knockdown of TXNDC12 inhibited the proliferation of U251 and A172 in vitro. On day 21 post-implantation, tumor growth inhibition was 70% in A172 with stable expression of TXNDC12 shRNA in vivo (P < 0.001). Kaplan-Meier analysis of survival data showed that the overall survival of tumor-bearing animals increased from 20.3 days (control) to 28.7 days (knockout, P < 0.05). These data suggest that TXNDC12 is a key mediator in redox homeostasis both in vivo and in vitro. Thus, TXNDC12 is a potential treatment target of GBM.

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Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines

Cited by 115 publications

References 50 publications

Identification of Iron Metabolism-Related Genes as Prognostic Indicators for Lower-Grade Glioma

Identification of Iron Metabolism-Related Genes as Prognostic Indicators for Lower-Grade Glioma

Autophagy-Dependent Ferroptosis-Related Signature is Closely Associated with the Prognosis and Tumor Immune Escape of Patients with Glioma

Loss of TXNDC12 Induces Oxidative Stress-mediated Autophagy in Glioblastoma Cell Lines

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