The Molecular Basis of Ubiquitin-Conjugating Enzymes (E2s) as a Potential Target for Cancer Therapy

Abstract

Ubiquitin-conjugating enzymes (E2s) are one of the three enzymes required by the ubiquitin-proteasome pathway to connect activated ubiquitin to target proteins via ubiquitin ligases. E2s determine the connection type of the ubiquitin chains, and different types of ubiquitin chains regulate the stability and activity of substrate proteins. Thus, E2s participate in the regulation of a variety of biological processes. In recent years, the importance of E2s in human health and diseases has been particularly emphasized. Studies have shown that E2s are dysregulated in variety of cancers, thus it might be a potential therapeutic target. However, the molecular basis of E2s as a therapeutic target has not been described systematically. We reviewed this issue from the perspective of the special position and role of E2s in the ubiquitin-proteasome pathway, the structure of E2s and biological processes they are involved in. In addition, the inhibitors and microRNAs targeting E2s are also summarized. This article not only provides a direction for the development of effective drugs but also lays a foundation for further study on this enzyme in the future.

Ubiquitin Proteasome Gene Signatures in Ependymoma Molecular Subtypes

“…Ubiquitin E2 conjugases affecting ubiquitination and SUMOylation of Proliferating Cell Nuclear Antigen (PCNA) were associated with ST-EPN-RELA subtype and affect the complex functions of PCNA at DNA replication forks and in DNA repair [ 122 , 123 ]. The ubiquitin E2 conjugases UBE2N and UBE2V2 contribute to ubiquitination of PCNA to allow the continuation of the DNA replication process across unrestored damaged DNA sites [ 124 , 125 ]. Expression of both UBE2V2 and UBE2I (aka SUMO Conjugating Enzyme, UBC9 ) were elevated in the ST_EPN_RELA compared to the other subtypes.…”

“…Expression of both UBE2V2 and UBE2I (aka SUMO Conjugating Enzyme, UBC9 ) were elevated in the ST_EPN_RELA compared to the other subtypes. UBE2I contributes to SUMOyation of PCNA and is a proposed therapeutic target in colon cancer [ 124 , 126 , 127 ] and the SUMO conjugating activity of UBE2I also contributes to DNA repair [ 128 ]. RNF8 expression was elevated in SP_EPN ( Figure 14 ).…”

Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma

“…1H; Additional file 2: Table S2). Indeed, ubiquitin-conjugating enzymes have been shown to be overexpressed in various cancer types and involved in the regulation of a variety of cancer-associated biological processes [39]. Overexpression of UBE2S, for instance, has been shown to reduce the stability and activity of the p53 protein by increasing its ubiquitination [40].…”

Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease

“…Это ведет к запуску процесса ЭМП на клетках РМЖ линии MCF-10A [17]. В исследованиях показано, что убиквитинконъюгированный энзим E2 C (UBE2C) функционирует как онкоген, промотирующий ЭМП путем прямого влияния на 5′-UTR транскрипт, кодирующий ZEB1 [18]. В дополнение к этому, экспрессия ZEB1 регулируется разнообразными микроРНК на посттранскрипционном уровне [19][20][21].…”