The roles of E3 ubiquitin ligases in cancer progression and targeted therapy

Abstract

Ubiquitination is one of the most important post‐translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy.

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

“…The overexpression of members of the ubiquitin system, as well as the expression of their mutant proteins, has been reported in several cancer types, where they correlate with malignant progression, poor survival and prognosis [ 107 , 108 , 109 ]. Since the activity or proteolysis of several oncoproteins and tumor-suppressor proteins is impaired by the deregulation of the ubiquitin system in cancer [ 48 ], numerous biological processes are altered, including the cell cycle [ 15 , 51 , 110 ], cell invasion and metastasis [ 110 , 111 ], cancer metabolism [ 112 , 113 ], cancer stem cell stemness [ 113 , 114 ], immunological tumor microenvironment [ 113 ], immune evasion [ 51 ], tumor-promoting inflammation [ 51 ] and evasion from apoptosis [ 51 , 110 ].…”

“…Defects in deubiquitination have effects on the NF-kB, AKT and BRCA signaling pathways [ 119 ]. For a more comprehensive description of the role of the ubiquitination system in cancer development and progression, readers are referred to specific reviews [ 15 , 51 , 110 , 111 , 112 , 113 , 114 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ].…”

“…In the last decades, a large number of drugs/molecules targeting the ubiquitination machinery have entered clinical trials against solid and hematological malignancies (for a review, the reader is referred to [ 51 , 110 , 122 , 125 , 126 , 152 , 153 ]) and several trials have been conducted and are currently ongoing to assess their safety, tolerability and therapeutic activity in cancer ( ). Within this growing number of trials, only a few have been completed and results are currently available ( Table 2 ).…”

“…Several components of the UPS (such as E1, E2, E3, proteasome and DUBs) have been investigated in preclinical and clinical studies as therapeutic targets in cancer treatment [ 51 , 125 , 126 , 127 , 153 ]. The therapeutic strategies developed so far are mainly based on: (i) the possibility of manipulating the ubiquitination machinery to regulate specific proteins involved in cancer development and progression, i.e., oncoproteins and oncosuppressors; and (ii) exploiting the vulnerability of cancer cells to develop synthetic lethality approaches.…”

“…In humans, genetic alterations, abnormal expression or dysfunction of E3 ubiquitin ligases and DUBs determine the onset and progression of many pathological conditions such as neurodegenerative diseases, immune-related pathologies and cancer [ 8 , 48 , 49 , 50 ]. For these reasons, the study of the ubiquitination machinery, as well as the molecular mechanisms underlying its activity and regulation, has been an area of intense research over the last two decades with the aim of developing new therapeutic approaches to treat such pathological conditions [ 50 , 51 , 52 , 53 ].…”