Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset

Abstract

The ubiquitin‐proteasome system is an important regulatory machinery involved in proteostasis and cellular signaling. Proteins are ubiquitinated via the concerted action of E1 ubiquitin‐activating enzymes, E2 ubiquitin‐conjugating enzymes, and E3 ubiquitin ligases. Although most of the studies to date focus on the significance of E3 ubiquitin ligases in disease development and therapeutic treatment, recent discoveries suggest that E2 ubiquitin‐conjugating enzymes might also be potential drug targets. The ubiquitin‐conjugating enzyme E2 O (UBE2O), an E3‐independent E2 (i.e. an E2/E3 hybrid enzyme), can directly mediate the ubiquitination of many substrates. These include 5′‐AMP‐activated protein kinase catalytic subunit α2 (AMPKα2), tumor suppressor ubiquitin carboxyl‐terminal hydrolase BAP1, mixed‐lineage leukemia (MLL) protein, SMAD family member 6 (SMAD6), transcription factor c‐Maf and aryl hydrocarbon receptor nuclear translocator‐like protein 1 (ARNTL or BMAL1), and free ribosomal proteins, which are ubiquitinated in distinct ways, thereby associating UBE2O with a variety of biological functions. Furthermore, UBE2O is frequently amplified or mutated in multiple cancers, and its high expression is associated with low survival rate of gastric, lung, breast, and prostate cancer patients. However, the molecular mechanisms by which UBE2O contributes to tumor initiation and progression are not fully elucidated. This review focuses on emerging insights from genetics, biochemistry, and cell biology to explore the biological functions of UBE2O and its therapeutic potential.

UBE2O targets Mxi1 for ubiquitination and degradation to promote lung cancer progression and radioresistance

“…Thus, our work provides evidence that UBE2O is a novel ubiquitin ligase which is responsible for the degradation of Mxi1. It has been documented that UBE2O is frequently amplified or overexpressed in several types of human cancer, which include bladder cancer, breast cancer, and liver cancer [13,30]. Our clinical data clearly show that UBE2O protein is overproduced and inversely correlated with Mxi1 expression in lung cancer.…”

Long non‑coding RNA profiles in plasma exosomes of patients with gastric high‑grade intraepithelial neoplasia

“…Proteins are ubiquitinated by the synergistic effect of ubiquitin-activating enzymes. The ubiquitin-conjugating enzyme, E2O, is regularly amplified or mutated in numerous tumors, such as breast, gastric, kidney and ovarian cancer, and its high expression level was associated with low survival rates in patients with gastric, lung, breast and prostate carcinoma ( 49 ). Furthermore, the expression of ubiquitin ligase tripartite motif 59 (TRIM59) was upregulated in human gastric tumor tissues compared with that in non-tumor tissues, and its levels have been associated with cancer development and patient survival period ( 50 ).…”

The Positive Correlations between the Expression of Histopathological Ubiquitin-Conjugating Enzyme 2O Staining and Prostate Cancer Advancement

“…Furthermore, immunohistochemical analysis of breast cancer samples determined high UBE20 expression [ 11 ]. Another database [ 19 ] analyzing cancer patient survival rates shows the clinical significance of UBE2O overexpression. In a substantial proportion of human cancers, UBE2O expression could impact both neoplastic malignancies and clinical outcomes.…”