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Eukaryotic translation initiation factor 4E binding protein 1  ( EIF4EBP1 ) encodes the 4EBP1 protein, a negative regulator of mRNA translation and a substrate of the mechanistic target of rapamycin (mTOR), whose function and relevance in cancer is still under debate. Here, we analyzed  EIF4EBP1  expression in different glioma patient cohorts and investigated its mode of transcriptional regulation in glioblastoma cells. We verified that  EIF4EBP1  mRNA is overexpressed in malignant gliomas, including isocitrate dehydrogenase (IDH)-wildtype glioblastomas, relative to non-neoplastic brain tissue in multiple publically available datasets. Our analyses revealed that  EIF4EBP1  overexpression in malignant gliomas is neither due to gene amplification nor to altered DNA methylation, but rather results from aberrant transcriptional activation by distinct transcription factors. We found seven transcription factor candidates co-expressed with  EIF4EBP1  in gliomas and bound to the  EIF4EBP1  promoter, as revealed by chromatin immunoprecipitation (ChIP)-sequencing data. We investigated the ability of these candidates to activate the  EIF4EBP1  promoter using luciferase reporter assays, which supported four transcription factors as candidate  EIF4EBP1  regulators, namely MYBL2, ETS1, HIF-1A, and E2F6. Finally, by employing transient knock-down experiments to repress either of these transcription factors, we identified MYBL2 and ETS1 as the relevant transcriptional drivers of enhanced  EIF4EBP1  expression in malignant glioma cells. Taken together, our findings confirm enhanced expression of  EIF4EBP1  in malignant gliomas relative to non-neoplastic brain tissue and characterize the underlying molecular pathomechanisms.

cell death discovery

Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) expression in glioblastoma is driven by ETS1- and MYBL2-dependent transcriptional activation