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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
Published on: May 1, 2020
The EIF4EBP1 gene encoding 4EBP1 is transcriptionally upregulated by MYC and linked to shorter survival in
Laura Hruby1, Katerina Schaal2, Alberto Delaidelli3,4,5
1Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Abstract:
Medulloblastoma (MB) is the most common malignant brain tumor in childhood and is stratified into four molecular groups ‒ Wingless and Int-1 (WNT), Sonic hedgehog (SHH), Group 3 and Group 4. Group 3 MB patients exhibit the poorest prognosis, with a 5-year overall survival of <60%, followed by Group 4 MB patients. Apart from MYC amplification in a subset of Group 3 MBs, the molecular pathomechanisms driving aggressiveness of these tumors remain incompletely characterized. The gene encoding the mTOR substrate and mRNA translation inhibitor eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) represents a possible MYC target gene whose corresponding protein, 4EBP1, was shown to be more active in Group 3 versus Group 4 MBs. However, the prognostic role of 4EBP1 in MB and the mechanisms supporting 4EBP1 overexpression in Group 3 MB are still elusive. We analyzed EIF4EBP1 mRNA expression in publicly available data sets and found an upregulation in MB as compared to non-neoblastic brain. EIF4EBP1 mRNA expression levels were higher in Group 3 compared to Group 4 MBs. EIF4EBP1 mRNA expression was correlated with MYC expression, most prominently in Group 3 MBs. Survival analyses highlighted that high EIF4EBP1 mRNA expression was associated with reduced overall and event-free survival across all MB patients and in Group 3/Group 4 MB patients. Immunohistochemical evaluation of 4EBP1 protein expression in MB tissues confirmed that high levels of 4EBP1 are associated with poor outcome. Functional analyses revealed that MYC directly regulates EIF4EBP1 promoter activity, providing a mechanism for increased EIF4EBP1 mRNA levels in Group 3 MBs. Finally, we observed that 4EBP1 may support colony formation of in vitro cultured MB cells. Our data highlight that transcriptional upregulation of EIF4EBP1 by MYC promotes in vitro tumorigenicity of MB cells and associates with shorter survival of MB patients.
Insights
MYC drives aggressive medulloblastoma (MB) by increasing eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1). High EIF4EBP1 levels correlate with poor prognosis in MB patients, indicating its role in tumor aggressiveness.
Area of Science:
- Pediatric neuro-oncology
- Cancer molecular biology
- Translational research
Background:
- Medulloblastoma (MB) is the most common malignant pediatric brain tumor.
- Group 3 MB has the poorest prognosis, with poorly understood drivers of aggressiveness.
- Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) is implicated but its role is unclear.
Purpose of the Study:
- To investigate the prognostic role of EIF4EBP1 in MB.
- To elucidate the mechanisms driving EIF4EBP1 overexpression in Group 3 MB.
- To assess the functional impact of EIF4EBP1 on MB cell tumorigenicity.
Main Methods:
- Analysis of publicly available EIF4EBP1 mRNA expression datasets.
- Correlation analysis with MYC expression and patient survival data.
- Immunohistochemistry for 4EBP1 protein.
- Functional assays for MB cell colony formation and promoter activity.
Main Results:
- EIF4EBP1 mRNA is upregulated in MB and higher in Group 3 vs. Group 4.
- High EIF4EBP1 expression correlates with reduced overall and event-free survival.
- MYC directly regulates EIF4EBP1 transcription, explaining overexpression in Group 3.
- 4EBP1 supports in vitro MB cell colony formation.
Conclusions:
- Transcriptional upregulation of EIF4EBP1 by MYC contributes to MB aggressiveness.
- EIF4EBP1 is a potential therapeutic target for high-risk medulloblastoma.
- High EIF4EBP1 expression is a marker of poor prognosis in MB patients.
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