Proteomic analysis uncovers enhanced inflammatory pheno-type and distinct metabolic changes in IDH1 mutant glioma cells

ABSTRACT: Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influenc-ing tumor aggressiveness and treatment response. To elucidate their molecular impact, we performed proteome analysis on patient-derived (PD) and U87MG glioma cell models with either mutant or wildtype IDH1. We quantified over 6,000 protein groups per model, identifying 1,594 differentially expressed proteins in PD-AS (IDH1MUT) vs. PD-GB (IDH1WT) and 904 in U87MUT vs. U87WT. Both IDH1MUT models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microen-vironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87MUT cells retained oxidative phosphory-lation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1MUT mod-els, particularly those involved in homologous recombination. In contrast, RB1 and AS-MTL were strongly upregulated in both IDH1MUT models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins reg-ulating histone methylation in IDH1MUT cells, favoring increased methylation of H3K4, H3K9, and H3K36. A key driver of this may be the upregulation of SETD2 in PD-AS, an H3K4 and H3K36 trimethyltransferase linked to recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways rele-vant to glioma progression and therapeutic targeting but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation sta-tus. While proteome profiling provides valuable insights, a comprehensive understand-ing of IDH1MUT gliomas will likely require integrative multi-omics approaches, including DNA/RNA methylation profiling, histone and protein post-translational modification analyses, and targeted DNA damage and repair assays.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Animesh Sharma  

LAB HEAD: Geir Slupphaug

PROVIDER: PXD065327 | Pride | 2025-10-06

REPOSITORIES: Pride