The role of E3 ubiquitin ligases in the development and progression of glioblastoma

Abstract

Despite recent advances in our understanding of the disease, glioblastoma (GB) continues to have limited treatment options and carries a dismal prognosis for patients. Efforts to stratify this heterogeneous malignancy using molecular classifiers identified frequent alterations in targetable proteins belonging to several pathways including the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signalling pathways. However, these findings have failed to improve clinical outcomes for patients. In almost all cases, GB becomes refractory to standard-of-care therapy, and recent evidence suggests that disease recurrence may be associated with a subpopulation of cells known as glioma stem cells (GSCs). Therefore, there remains a significant unmet need for novel therapeutic strategies. E3 ubiquitin ligases are a family of >700 proteins that conjugate ubiquitin to target proteins, resulting in an array of cellular responses, including DNA repair, pro-survival signalling and protein degradation. Ubiquitin modifications on target proteins are diverse, ranging from mono-ubiquitination through to the formation of polyubiquitin chains and mixed chains. The specificity in substrate tagging and chain elongation is dictated by E3 ubiquitin ligases, which have essential regulatory roles in multiple aspects of brain cancer pathogenesis. In this review, we begin by briefly summarising the histological and molecular classification of GB. We comprehensively describe the roles of E3 ubiquitin ligases in RTK and MAPK, as well as other, commonly altered, oncogenic and tumour suppressive signalling pathways in GB. We also describe the role of E3 ligases in maintaining glioma stem cell populations and their function in promoting resistance to ionizing radiation (IR) and chemotherapy. Finally, we consider how our knowledge of E3 ligase biology may be used for future therapeutic interventions in GB, including the use of blood–brain barrier permeable proteolysis targeting chimeras (PROTACs).

TRIM28 Selective Nanobody Reduces Glioblastoma Stem Cell Invasion

“…Transcription factor TRIM28 is a part of tripartite motif (TRIM) containing a protein superfamily, which contains approximately 70 members [ 30 , 31 , 32 ]. Detected in cell nuclei but not in cytoplasm, TRIM28 serves as an important factor in the posttranslational mechanism to regulate various cell functions, such as transcriptional regulation of p53 suppression by promoting its ubiquitination and degradation [ 44 , 45 ]. In addition, TRIM28 has an important role in the oncogenesis in different cancer types [ 46 , 47 ].…”

CRISPR Screening of E3 Ubiquitin Ligases Reveals Ring Finger Protein 185 as a Novel Tumor Suppressor in Glioblastoma Repressed by Promoter Hypermethylation and miR-587

“…Post-translational modi cations, including protein ubiquitination, are well-known for its role in protein metabolism, especially in protein degradation [48]. As a hub link in protein ubiquitination and signaling transduction, the alteration of E3 ubiquitin ligases are emerging as oncogenes and tumor suppressors in cancer, including glioblastoma [14,49]. Meanwhile, technological advances proposed novel strategies for the undruggable targets in cancer, such as ubiquitin modi ers and transcription factors [50,51].…”

“…The ubiquitin-proteasome system regulates many cellular processes, including cell cycle, differentiation, DNA repair, and the immune response in cancer [13]. Accumulating evidence shows that E3 ligases play important functions in glioma pathogenesis, progression, therapy response and prognostic marker [14].…”

Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

“…Aberrations of ubiquitin signalling are often associated with pathogenesis of several diseases and genetic disorders [58,[70][71][72][73]. Errors in ubiquitin signalling processes result in defective autophagy and mitophagy, DNA repair mechanisms, NF-kB signalling, etc.…”