The Ubiquitin-Conjugating Enzyme E2 O (UBE2O) and Its Therapeutic Potential in Human Leukemias and Solid Tumors

Abstract

Protein degradation is a biological phenomenon essential for cellular homeostasis and survival. Selective protein degradation is performed by the ubiquitination system which selectively targets proteins that need to be eliminated and leads them to proteasome degradation. In this narrative review, we focus on the ubiquitin-conjugating enzyme E2 O (UBE2O) and highlight the role of UBE2O in many biological and physiological processes. We further discuss UBE2O's implications in various human diseases, particularly in leukemias and solid cancers. Ultimately, our review aims to highlight the potential role of UBE2O as a therapeutic target and offers new perspectives for developing targeted treatments for human cancers.

Keywords: UBE2O; UPS; erythropoiesis; leukemia; protein degradation; solid tumors; ubiquitin.

Figure 1

UBE2O exerts both enzymatic functions and non-enzymatic functions. The most studied and reported function of UBE2O is that as a hybrid E2/E3 enzyme, it catalyzes substrates ubiquitination. Nonetheless, UBE2O has been shown to also exert non-enzymatic functions. Figure 1 shows two examples of different functions of UBE2O. The enzymatic function is explained through the depiction of the AMPK-mTOR pathway, in which UBE2O catalyzes the ubiquitination of AMPK, thus inducing its degradation and the activation of mTOR and subsequently of HIF1α. The non-enzymatic function of UBE2O is represented through the schematization of the interaction of the UBE2O N-terminal fraction with TRAF6, thus impeding its ubiquitination and negatively regulating the NF-κB pathway. AMPK: 5′ adenosine monophosphate-activated protein kinase; CC: coiled-coil region; CR1/2/3: conserved region 1/2/3; HIF1α: hypoxia-inducible factor 1-alpha; mTOR: mammalian target of rapamycin; NLS: nuclear localization sequence; NF-kB: nuclear factor kappa-light enhancer of activated B cells; TRAF6: tumor necrosis factor receptor-associated factor 6; UB: ubiquitin; UBE2O: ubiquitin-conjugating enzyme E2 O; UBC: ubiquitin-conjugating core domain. Created with “www.BioRender.com (accessed on 28 August 2024)”.

Figure 2

UBE2O in hematology under physiological and pathological conditions. A fine regulation of protein turnover and degradation is essential for maintaining cells’ homeostasis. Regarding an alteration at this level, UBE2O is important in many aspects of hematology. (A) UBE2O is essential for proper erythroid differentiation. Hence, UBE2O silencing leads to the incapability of generating red blood cells. UBE2O: ubiquitin-conjugating enzyme E2 O. (B) Overexpression of UBE2O in AML cells inhibits leukemic cells’ proliferation and induces apoptosis. AML: acute myeloid leukemia; BM: bone marrow; MSCs: mesenchymal stromal cells; NF-κB: nuclear factor kappa B; (C) UBE2O activity promotes c-Maf polyubiquitination and the subsequent apoptosis of MM cells. ARK: AMPK-related protein kinase 5; CCR1: C-C Motif Chemokine Receptor 1; MM: multiple myeloma. (D) UBE2O depletion promotes the stability of wild-type KMT2A in hematological neoplasia characterized by KMT2A rearrangements. IL-1β: interleukin-1β; IRAKs: interleukin-1 receptor-associated kinases; KMT2A: lysine methyltransferase 2A; WT: wild-type. Created with “www.BioRender.com (accessed on 28 August 2024)”.

Figure 3

UBE2O in non-blood diseases. Overview of UBE2O mechanism of action in non-hematological diseases: lower left: hepatocellular carcinoma; upper left: lung cancer; center: Alzheimer disease; upper right: breast cancer; lower right: type 2 diabetes. Aβ: amyloid-β; AD: Alzheimer’s disease; AMPKα2: AMP-activated protein kinase alpha 2; HADHA: hydroxyacyl-CoA dehydrogenase; IFIT3: interferon-induced protein; IFN-α: interferon-alpha; mTORC1: mammalian target of rapamycin complex 1; Mxi1: MAX interactor 1; MYC: also known as cMyc. Created with “www.BioRender.com (accessed on 28 August 2024)”.