A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates in Glioma Therapy

Krassnig, Stefanie; Wohlrab, Christina; Golob-Schwarzl, Nicole; Raicht, Andrea; Schatz, Christoph; Birkl-Toeglhofer, Anna Maria; Skofler, Christina; Gantenbein, Nadine; Leoni, Marlene; Asslaber, Martin; Leber, Stefan; Mahdy-Ali, Kariem; Campe, Gord von; Mayer, M.; Borenich, Andrea; Weis, Serge; Benesch, Martin; Haybaeck, Johannes

doi:10.3390/cancers13061482

Cited by 12 publications

(10 citation statements)

References 39 publications

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“… 18 Transcriptional factors, eukaryotic initiation factors, have been regarded as promising targets for glioma patients through regulation of PI3K/AKT/mTOR pathway. 19 WSTF promoted epithelial to mesenchymal transition of lung cancer through activation of PI3K/AKT pathway. 20 Therefore, WSTF might be involved in gliomagenesis through PI3K/AKT pathway.…”

Section: Discussionmentioning

confidence: 96%

Downregulation of Williams syndrome transcription factor (WSTF) suppresses glioblastoma cell growth and invasion by inhibiting PI3K/AKT signal pathway

Yang¹,

Du²,

Chen³

et al. 2021

Eur J Histochem

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Williams syndrome transcription factor (WSTF) participates in diverse cellular processes, including tumor cell proliferation and migration. However, the function of WSTF in glioblastoma (GBM) remains unknown. Data from the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) datasets showed that WSTF was up-regulated in GBM tissues. Moreover, WSTF was also increased in the GBM cells. pcDNA-mediated over-expression of WSTF contributed to cell proliferation and invasion of GBM cells, while GBM cell proliferation and invasion were suppressed by shRNA-mediated silencing of WSTF. Additionally, GBM cell apoptosis was reduced by over-expression of WSTF accompanied by decrease in Bax and cleaved caspase-3, while promoted by silencing of WSTF with increase in Bax and cleaved caspase-3. Protein expression of AKT phosphorylation was enhanced by WSTF over-expression while reduced by WSTF silencing. Inhibitor of phosphatidylinositol 3 kinase attenuated WSTF over-expression-induced increase in GBM cell proliferation and invasion. In conclusion, WSTF contributed to GBM cell growth and invasion through activation of PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 96%

Downregulation of Williams syndrome transcription factor (WSTF) suppresses glioblastoma cell growth and invasion by inhibiting PI3K/AKT signal pathway

Yang¹,

Du²,

Chen³

et al. 2021

Eur J Histochem

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“…These results indicate that EIF4A1 might have an oncogenic function in LUAD by influencing cell division. EIF4A1 helicase activity is required for the pathogenic function of EIF4A1 by synergizing EIF4A to unwind secondary structures or facilitate the translation of a subset of oncogenic mRNAs [ 36 ]. The helicase activity of EIF4A1 is enhanced by EIF4H, which can interact with EIF4A by increasing the affinity of EIF4A for RNA [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…The helicase activity of EIF4A1 is enhanced by EIF4H, which can interact with EIF4A by increasing the affinity of EIF4A for RNA [ 37 ]. Reportedly, EIF4H is overexpressed in various cancers, such as colorectal cancer and glioma [ 36 , 38 ]. The splicing factor, RNA binding motif protein 10 (RBM10), suppresses LUAD progression by regulating alternative splicing of EIF4H exon 5 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming

Huang

et al. 2022

Biology

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Lung adenocarcinoma (LUAD) is a common type of lung cancer. Although the diagnosis and treatment of LUAD have significantly improved in recent decades, the survival for advanced LUAD is still poor. It is necessary to identify more targets for developing potential agents against LUAD. This study explored the dysregulation of translation initiation factors, specifically eukaryotic initiation factors 4A1 (EIF4A1) and EIF4A2, in developing LUAD, as well as their underlying mechanisms. We found that the expression of EIF4A1, but not EIF4A2, was higher in tumor tissue and associated with poor clinical outcomes in LUAD patients. Elevated expression of EIF4H with poor prognosis may potentiate the oncogenic role of EIF4A1. Functional enrichment analysis revealed that upregulation of EIF4A1 was related to cell cycle regulation and DNA repair. The oncogenic effect of EIF4A1 was further elucidated by Gene Set Variation Analysis (GSVA). The GSVA score of the gene set positively correlated with EIF4A1 was higher in tumors and significantly associated with worse survival. In the meantime, gene set enrichment analysis (GSEA) also indicated that elevated EIF4A1 expression in LUAD patients was associated with a decreased infiltration score for immune cells by reducing anticancer immune cell types and recruiting immunosuppressive cells. Consistent with the results, the GSVA score of genes whose expression was negatively correlated with EIF4A1 was lower in the tumor tissue of LUAD cases with worse clinical outcomes and was strongly associated with the disequilibrium of anti-cancer immunity by recruiting anticancer immune cells. Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

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“…The mRNAs of all eIF3 subunits, except subunit k, are significantly overexpressed in GB ( Digregorio et al, 2019 ), and the levels of eIF3 proteins are increased in high-grade gliomas ( Krassnig et al, 2021 ). These observations are important because the following eIF3 subunits have been involved in GB progression ( Figure 3 ).…”

Section: Translation and Gb In The Spotlightmentioning

confidence: 99%

The dark side of mRNA translation and the translation machinery in glioblastoma

Montiel-Dávalos

Ayala²,

Hernández³

2023

Front. Cell Dev. Biol.

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Among the different types of cancer affecting the central nervous system (CNS), glioblastoma (GB) is classified by the World Health Organization (WHO) as the most common and aggressive CNS cancer in adults. GB incidence is more frequent among persons aged 45–55 years old. GB treatments are based on tumor resection, radiation, and chemotherapies. The current development of novel molecular biomarkers (MB) has led to a more accurate prediction of GB progression. Moreover, clinical, epidemiological, and experimental studies have established genetic variants consistently associated with the risk of suffering GB. However, despite the advances in these fields, the survival expectancy of GB patients is still shorter than 2 years. Thus, fundamental processes inducing tumor onset and progression remain to be elucidated. In recent years, mRNA translation has been in the spotlight, as its dysregulation is emerging as a key cause of GB. In particular, the initiation phase of translation is most involved in this process. Among the crucial events, the machinery performing this phase undergoes a reconfiguration under the hypoxic conditions in the tumor microenvironment. In addition, ribosomal proteins (RPs) have been reported to play translation-independent roles in GB development. This review focuses on the research elucidating the tight relationship between translation initiation, the translation machinery, and GB. We also summarize the state-of-the-art drugs targeting the translation machinery to improve patients’ survival. Overall, the recent advances in this field are shedding new light on the dark side of translation in GB.

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A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates in Glioma Therapy

Cited by 12 publications

References 39 publications

Downregulation of Williams syndrome transcription factor (WSTF) suppresses glioblastoma cell growth and invasion by inhibiting PI3K/AKT signal pathway

Downregulation of Williams syndrome transcription factor (WSTF) suppresses glioblastoma cell growth and invasion by inhibiting PI3K/AKT signal pathway

Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming

The dark side of mRNA translation and the translation machinery in glioblastoma

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