Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Rm34, BMSB, 745 Bannatyne Ave, Winnipeg, MB, R3E0J9, Canada.
Cell Mol Neurobiol. 2023 May;43(4):1425-1452. doi: 10.1007/s10571-022-01261-0. Epub 2022 Jul 27.
We have mined public genomic datasets to identify genes coding for components of the ubiquitin proteasome system (UPS) that may qualify as potential diagnostic and therapeutic targets in the three major glioma types, astrocytoma (AS), glioblastoma (GBM), and oligodendroglioma (ODG). In the Sun dataset of glioma (GEO ID: GSE4290), expression of the genes UBE2S and UBE2C, which encode ubiquitin conjugases important for cell-cycle progression, distinguished GBM from AS and ODG. KEGG analysis showed that among the ubiquitin E3 ligase genes differentially expressed, the Notch pathway was significantly over-represented, whereas among the E3 ligase adaptor genes the Hippo pathway was over-represented. We provide evidence that the UPS gene contributions to the Notch and Hippo pathway signatures are related to stem cell pathways and can distinguish GBM from AS and ODG. In the Sun dataset, AURKA and TPX2, two cell-cycle genes coding for E3 ligases, and the cell-cycle gene coding for the E3 adaptor CDC20 were upregulated in GBM. E3 ligase adaptor genes differentially expressed were also over-represented for the Hippo pathway and were able to distinguish classic, mesenchymal, and proneural subtypes of GBM. Also over-expressed in GBM were PSMB8 and PSMB9, genes encoding subunits of the immunoproteasome. Our transcriptome analysis provides a strong rationale for UPS members as attractive therapeutic targets for the development of more effective treatment strategies in malignant glioma. Ubiquitin proteasome system and glioblastoma: E1-ubiquitin-activating enzyme, E2-ubiquitin-conjugating enzyme, E3-ubiquitin ligase. Ubiquitinated substrates of E3 ligases may be degraded by the proteasome. Expression of genes for specific E2 conjugases, E3 ligases, and genes for proteasome subunits may serve as differential markers of subtypes of glioblastoma.
我们挖掘了公共基因组数据集，以鉴定编码泛素蛋白酶体系统 (UPS) 成分的基因，这些基因可能成为三种主要胶质瘤类型（星形细胞瘤 (AS)、胶质母细胞瘤 (GBM) 和少突胶质细胞瘤 (ODG)）的潜在诊断和治疗靶点。在 Sun 等人的胶质瘤数据集（GEO ID：GSE4290）中，编码对细胞周期进程重要的泛素缀合酶的基因 UBE2S 和 UBE2C 的表达将 GBM 与 AS 和 ODG 区分开来。KEGG 分析表明，在差异表达的泛素 E3 连接酶基因中，Notch 途径显著过表达，而在 E3 连接酶衔接子基因中，Hippo 途径过表达。我们提供的证据表明，UPS 基因对 Notch 和 Hippo 途径特征的贡献与干细胞途径有关，并且可以区分 GBM 与 AS 和 ODG。在 Sun 等人的数据集，细胞周期基因 AURKA 和 TPX2 编码 E3 连接酶，以及编码 E3 衔接子 CDC20 的细胞周期基因在 GBM 中上调。差异表达的 E3 连接酶衔接子基因也过表达 Hippo 途径，能够区分经典、间充质和神经前体 GBM 亚型。在 GBM 中过度表达的还有编码免疫蛋白酶体亚基的 PSMB8 和 PSMB9 基因。我们的转录组分析为 UPS 成员作为恶性神经胶质瘤更有效治疗策略的有吸引力的治疗靶点提供了强有力的依据。泛素蛋白酶体系统和胶质母细胞瘤：E1-泛素激活酶、E2-泛素缀合酶、E3-泛素连接酶。E3 连接酶的泛素化底物可能被蛋白酶体降解。特定 E2 缀合酶、E3 连接酶和蛋白酶体亚基基因的表达可作为胶质母细胞瘤亚型的差异标记。
