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.

Mechanism study of ubiquitination in T cell development and autoimmune disease

“…It is worth noting that drugs targeting the ubiquitin-proteasome system has shown promise in the treatment of autoimmune disorders and cancers, such as bendamustine (targeting LUBAC), thalidomide (targeting CRBN), and mitoxantrone (targeting USP11, USP15) et al. ( 23 – 25 ). In this review, we discuss the importance of ubiquitination in T cell development ( Figure 3 ) and self-tolerance establishment ( Figure 4 ), with an emphasis on the mechanism studies of T cell progenitors, thymic selections, proliferation, apoptosis, Treg development and TEC functions.…”

The prognostic value of ubiquitin/ubiquitin-like-related genes along with immune cell infiltration and clinicopathological features in osteosarcoma

“…Many vital cellular functions, such as DNA repair, cell cycle progression, cell proliferation and cell apoptosis, are regulated in this way [ 10 , 11 ]. Moreover, dysregulation of these functions is closely related to cancer [ 9 , 12 – 18 ]. More importantly, several Ub/UBL-related genes have recently been shown to have prognostic value in osteosarcoma [ 19 – 22 ].…”