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

Abstract

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.

Deciphering Glioblastoma: Fundamental and Novel Insights into the Biology and Therapeutic Strategies of Gliomas

“…Given that IDH -mutated and IDH wildtype gliomas display distinct mutation profiles and clinical trajectories, they are considered to develop through separate oncogenic mechanisms, thus representing distinct entities despite their histopathological similarities [ 20 ]. A study by Vriend and Klonisch presents evidence indicating that contributions from genes in the ubiquitin proteasome system (UPS) to the Notch and Hippo pathway signatures are interconnected with stem cell pathways and possess the capability to differentiate GBM from AS and ODG [ 21 ]. Their analysis revealed that AURKA and TPX2 (two cell-cycle genes encoding for E3 ligases, as well as the cell-cycle gene responsible for encoding the E3 adaptor CDC20) are upregulated in GBM.…”

“…Their analysis revealed that AURKA and TPX2 (two cell-cycle genes encoding for E3 ligases, as well as the cell-cycle gene responsible for encoding the E3 adaptor CDC20) are upregulated in GBM. Further, genes associated with E3 ligase adaptors, exhibiting differential expression, demonstrated a significant overrepresentation in the Hippo pathway, contributing to the distinction of classic, mesenchymal, and proneural subtypes of GBM [ 21 ].…”

Role of UBE2C in Brain Cancer Invasion and Dissemination

“…Interestingly, FoxM1 is upregulated in brain tumors, particularly GB and meningioma [75,106]. Upregulation of UBE2C is observed in GB tissues, mainly in the proneural subtype, characterized by neurogenesis-related gene expression and increased invasion [107,108]. The combined upregulation of UBE2C and aurora kinase B (AURKB), an important player in the cell cycle, is associated with a dismal outcome, therapeutic resistance, and reduced overall survival in glioma patients [76].…”

Intersections of Ubiquitin-Proteosome System and Autophagy in Promoting Growth of Glioblastoma Multiforme: Challenges and Opportunities

“…Multiple studies have shown that GBM cells exhibit changes in the expression of genes associated with UPS [ 13 , 14 ]. Ubiquitin, a highly conserved protein with a length of 76 amino acids, is expressed in all cell types and ubiquitination, the attachment of ubiquitin to a substrate, is one of the most common post-translational modifications of proteins.…”