The role of ubiquitination in tumorigenesis and targeted drug discovery

Abstract

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

F-Box Proteins and Cancer

“…Various F-box proteins have tumor-suppressive or oncogenic functions and have therefore been proposed as potential anticancer targets, with several inhibitors of these proteins having been developed [265]. However, none of these agents have yet entered clinical studies, with the field still being at an early stage.…”

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

“…Also, proteasome inhibitors, PIs (bortezomib, oprozomib, ixazomib, etc.) have shown promising results in clinics but some side effects limit their widespread application ( 191 ). Another PI marizomib, which can cross BBB and shows fewer side effects, has been applied to treat newly diagnosed GB (NCT03345095).…”

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

“…Targeted protein degradation is an emerging field that is expected to revolutionize how “undruggable” proteins can be targeted in diseases such as cancer. Indeed, it promises to be the greatest innovation in small-molecule drug discovery in the new millennium [ 61 , 62 ]. Cancer therapeutics targeting EMT-related E3 ubiquitin-ligases have been elucidated as a promising strategy to treat cancer, as they allow for the elimination of off-target side effects, compared to the strategy using anti-E1 and anti-E2, or an anti-proteasome subunit.…”