eEF1A1K165 methylation modulator of protein synthesis and promoter of glioma tumorigenesis

Project Details

Description

Gliomas are the most common primary brain tumours and present very poor prognosis. Mutations in the isocitrate dehydrogenase 1 (IDH1) are primary events in gliomagenesis. They lead to an accumulation of the oncometabolite 2-hydroxyglutarate (2HG) that is associated to an increased methylation of DNA and histone tails. We hypothesized that high levels of 2HG also influence the methylation of other relevant non-histone proteins.
In the last two years, we investigated changes in the lysine-methylation of non-histone proteins in response to high levels of 2HG in gliomas. We identified 554 methylated proteins in glioma cell lines. Several proteins presented significant differences in the lysine methylation between IDH1wt and IDH1mutant cell lines. Among them, methylation of lysine 165 (K165) of the eukaryotic elongation factor 1 alpha (eEF1A), a key player in translation, showed the strongest regulation by 2HG. We demonstrated that glioma cell lines and tissue samples from glioma patients are characterized by a high methylation rate of eEF1A1 K165. In agreement withthat, the specific methyltransferase of eEF1A1 K165, METTL21B, is upregulated in glioma patients compared to adjacent normal brain and its levels are highly associated with patient survival.
In the proposed project we aim to investigate the specific role of the methylation in eEF1A1 K165 and METTL21B in protein translation and glioma progression. We will first generate two models to prevent or decrease the methylation rate in eEF1A1 K165: point mutations to substitute the lysine residue K165 with alanine or glutamine, and knock-down constructs for METTL21B. Using these two models, we will investigate the role of K165 methylation in protein synthesis using RiboSeq and dynamic SILAC studies, and in cell proliferation and general tumor growth. In parallel, we will evaluate the levels of the different eEF1A1 methyltransferases in clinical samples and their correlation with patient survival.
AcronymMETGLIO
StatusActive
Effective start/end date1/01/2014/06/23

Funding

  • FNRS - Fonds National de la Recherche Scientifique: €73,580.00
  • FNRS - Fonds National de la Recherche Scientifique: €175,774.00

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