Vriend Jerry, Thanasupawat Thatchawan, Sinha Namita, Klonisch Thomas
Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P5, Canada.
Int J Mol Sci. 2022 Oct 15;23(20):12330. doi: 10.3390/ijms232012330.
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 , , and 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 and the F-box cullin ring ligase adaptor . Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome 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.
泛素蛋白酶体系统（UPS）对细胞内稳态至关重要，几乎影响正常细胞和肿瘤细胞的所有关键功能。目前，缺乏对UPS在室管膜瘤（EPN）脑肿瘤中作用的全面综述，但这可能会为不同EPN亚型特有的细胞网络提供有价值的新信息，并揭示未来的治疗靶点。我们回顾了公开可用的编码UPS途径成分的EPN基因转录数据集。对这些数据的Reactome分析揭示了能够高度显著地区分不同EPN亚型的基因和途径。我们鉴定了几个与EPN亚型相关的编码泛素E2缀合酶的基因的差异转录。E2缀合酶基因UBE2C、UBE2S和UBE2I在ST_EPN_RELA亚型中表达升高。UBE2C和UBE2S酶与泛素连接酶后期促进复合物（APC/c）相关，后者调节与细胞周期进程相关的底物的降解，而UBE2I是一种SUMO缀合酶。此外，ST_EPN_RELA中E3连接酶、组蛋白脱乙酰酶HDAC4和F-box cullin环连接酶衔接蛋白FBXO22的基因也升高。聚类分析表明，几个编码E3连接酶及其底物衔接蛋白的基因是EPN亚型特异性遗传标记。与E3连接酶及其衔接蛋白的差异表达基因相关的最显著的Reactome途径包括抗原呈递、NEDDylation、SUMOylation和APC/c复合物。我们的分析提供了几个与UPS相关的因素，这些因素可能是有吸引力的标记物，也是EPN患者亚型特异性治疗的未来治疗靶点。
