Ravn Berg Sigrid, Brambilla Alessandro, Hagen Lars, Sharma Animesh, Vågbø Cathrine Broberg, Liabakk Nina Beate, Kissova Miroslava, Arano Barenys Miquel, Bjørås Magnar, Torp Sverre Helge, Slupphaug Geir
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Clinic of Laboratory Medicine, St. Olavs Hospital, 7491 Trondheim, Norway.
Int J Mol Sci. 2025 Sep 18;26(18):9075. doi: 10.3390/ijms26189075.
Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influencing 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 wild-type IDH1. We quantified over 6000 protein groups per model, identifying 1594 differentially expressed proteins in PD-AS (IDH1) vs. PD-GB (IDH1) and 904 in U87 vs. U87. Both IDH1 models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microenvironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87 cells retained oxidative phosphorylation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1 models, particularly those involved in homologous recombination. In contrast, RB1 and ASMTL were strongly upregulated in both IDH1 models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins regulating histone methylation in IDH1 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 the recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways relevant to glioma progression and therapeutic targeting, but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation status. While proteome profiling provides valuable insights, a comprehensive understanding of IDH1 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.
异柠檬酸脱氢酶1（IDH1）突变是胶质瘤生物学的关键驱动因素，影响肿瘤侵袭性和治疗反应。为阐明其分子影响，我们对具有突变型或野生型IDH1的患者来源（PD）和U87MG胶质瘤细胞模型进行了蛋白质组分析。我们每个模型定量了6000多个蛋白质组，在PD-AS（IDH1）与PD-GB（IDH1）中鉴定出1594个差异表达蛋白质，在U87与U87中鉴定出904个差异表达蛋白质。两个IDH1模型均表现出增强的MHC抗原呈递和干扰素信号传导，表明免疫微环境发生改变。然而，代谢改变是模型依赖性的：PD-AS细胞向糖酵解和嘌呤补救转变，而U87细胞保留氧化磷酸化，这可能是由于D2-羟基戊二酸（2OHG）介导的HIF1A稳定化。我们还观察到IDH1模型中DNA修复蛋白主要下调，特别是那些参与同源重组的蛋白。相反，RB1和ASMTL在两个IDH1模型中均强烈上调，表明它们参与DNA修复和细胞应激反应。我们还发现IDH1细胞中调节组蛋白甲基化的蛋白质有不同的表达模式，有利于H3K4、H3K9和H3K36甲基化增加。其一个关键驱动因素可能是PD-AS中SETD2的上调，SETD2是一种H3K4和H3K36三甲基转移酶，与HIF1A以及DNA错配修复蛋白的募集有关。本研究揭示了与胶质瘤进展和治疗靶点相关的候选生物标志物和途径，但也强调了基于IDH1突变状态预测胶质瘤发病机制和治疗反应的复杂性。虽然蛋白质组分析提供了有价值的见解，但对IDH1胶质瘤的全面理解可能需要综合多组学方法，包括DNA/RNA甲基化分析、组蛋白和蛋白质翻译后修饰分析以及靶向DNA损伤和修复检测。
