Targeting the Ubiquitin-Proteasome System and Recent Advances in Cancer Therapy

Abstract

Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects on various signaling pathways. Ubiquitination can alter the molecular functions of tagged substrates with respect to protein turnover, biological activity, subcellular localization or protein-protein interaction. As a result, a wide variety of cellular processes are under ubiquitination-mediated control, contributing to the maintenance of cellular homeostasis. It follows that the dysregulation of ubiquitination reactions plays a relevant role in the pathogenic states of human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, the enzymes of the ubiquitin-proteasome system (UPS), including E3 ubiquitin ligases and deubiquitinases (DUBs), have attracted attention as novel druggable targets for the development of new anticancer therapeutic approaches. This perspective article summarizes the peculiarities shared by the enzymes involved in the ubiquitination reaction which, when deregulated, can lead to tumorigenesis. Accordingly, an overview of the main pharmacological interventions based on targeting the UPS that are in clinical use or still in clinical trials is provided, also highlighting the limitations of the therapeutic efficacy of these approaches. Therefore, various attempts to circumvent drug resistance and side effects as well as UPS-related emerging technologies in anticancer therapeutics are discussed.

Keywords: cancer; proteasome-mediated degradation; protein post-translational modifications; synthetic lethality; therapeutic approaches; ubiquitination.

Figure 1

Ubiquitination reaction and fate of targeted substrates based on the ubiquitin (Ub) chains. The scheme illustrates the enzymatic reaction involving the E1 ubiquitin-activating enzyme (E1), the E2 ubiquitin-conjugating enzyme (E2) and the E3 ubiquitin-ligases (E3). As two distinct mechanisms of ubiquitin ligation may occur, two examples are reported herein. Then, based on the number of ubiquitin residues and linkage specificity, targeted substrate may undergo the DUB-mediated removal of ubiquitin (upper panel on the right) or it can be degraded by proteasome with the release of free ubiquitin moieties (lower panel on the right).

Figure 2

DUB specificity. DUBs perform the removal of ubiquitin from targets on the basis of the specificity of linkage (left panel), the mode of action, which refers to removal of the distal ubiquitin (EXO) or internal ubiquitin along the chain (ENDO) or the proximal ubiquitin (EN-BLOC) (central panel), the interaction with targeted proteins with or without the assistance of adaptors (right panel).

Figure 3

Ubiquitination code. (A) The amino acid residues of ubiquitin involved in the modification are reported. The different types of ubiquitin chains with topologies are shown (B–D). The schematic representation illustrates the linkage specificity associated with the corresponding cellular functions: (B) monoubiquitination and multi-monoubiquitination, (C) homotypic polyubiquitination, (D) heterotypic polyubiquitination.

Figure 4

Therapeutic modalities targeting ubiquitin–proteasome system. The schematic representation summarizes the different strategies adopted to target the enzymes involved in the UPS. FDA-approved molecules, compounds entered in clinical trials, both cited as small molecules, as well as recently discovered approaches including synthetic lethality and UbV-mediated modulation of UPS proteins are indicated. More details are provided in the text. Created with BioRender.com, accessed 10 December 2023.