Ubiquitin Proteasome Gene Signatures in Ependymoma Molecular Subtypes

Abstract

The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes UBE2C, UBE2S, and UBE2I was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase HDAC4 and the F-box cullin ring ligase adaptor FBX031. Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome Pathways associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients.

Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug Resistant Human Breast Cancer

“…Another explanation for why elevated CDC20 levels promote cancer progression is that CDC20 accumulation reflects compromised APC activity, and is not therefore able to target CDC20 (or its other targets) for degradation, which is consistent with the overabundance of multiple APC substrates observed in unrelated cancer tissues. While CDC20 may be pro-oncogenic, it is unlikely to act in isolation, as at least 60 of the known 69 human APC substrates are associated with multiple cancer types when they accumulate [20], and are now considered a cancer signature [73,74]. A recent series of papers found that APC substrate-mRNAs, including HURP and CDC20, are elevated in multiple cancers, and are now recognized as a hub or signature gene set predictive of poor prognosis cancer (a subset of references are included here; [75][76][77][78]).…”

DUBing Primary Tumors of the Central Nervous System: Regulatory Roles of Deubiquitinases

“…Although these responses may initially be engaged to aid cellular stress adaptation, cancer cells usurp and/or co-opt these pathways for their benefit in numerous ways. We recently identified distinct gene expression changes in ubiquitin ligases and ligase adaptors in different human brain tumors and subtypes [42,43]. Sustained UPR signaling has been reported in diverse cancers, including breast, prostate, and brain cancers, and emerging evidence links ERAD and UPR to an array of pro-tumorigenic processes, including angiogenesis, metastasis, and cancer stem cell expansion [38].…”