Genes of the Ubiquitin Proteasome System Qualify as Differential Markers in Malignant Glioma of Astrocytic and Oligodendroglial Origin

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. GRAPHICAL ABSTRACT: 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. [Image: see text]