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

Abstract

The epithelial–mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer.

USP41 Enhances Epithelial–Mesenchymal Transition of Breast Cancer Cells through Snail Stabilization

“…Various targets involved in EMT are regulated by diverse E3 ligases through ubiquitination-mediated protein degradation, thereby modulating the EMT process [ 29 ]. Snail, a major transcription factor of EMT, can especially be controlled through the transcriptional or post-translational levels.…”

Protein Degradation by E3 Ubiquitin Ligases in Cancer Stem Cells

“…RING1 binds to the E2 conjugating enzyme and shows the same features of RING-type E3s. However, the RING2 domain behaves as an HECT domain, since it first forms a thioester bond intermediate with the ubiquitin recruited by RING1 and then transfers the ubiquitin to the substrate protein [ 39 , 40 , 41 , 42 , 43 ].…”

“…For instance, the ubiquitination of the core transcription factors, Nanog, Oct4 and Sox2, is involved in the maintenance of the stemness and pluripotency of stem cells [ 51 , 52 ]. Given that several contributions have recapitulated the contribution of the E3 ubiquitin ligases in cancer, epithelial-to-mesenchymal plasticity and embryonic stem cells, this issue will be not further discussed [ 10 , 42 , 53 ]. In this review, we will go in depth into the implication of the E3 ubiquitin ligases in cancer stem cells.…”

The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer

“…Ubiquitin ligases can promote the degradation of either oncogenes or tumorsuppressor genes, thus E3s are themselves "druggable" enzymes or serve as potential cancer targets [37,38]. The E3 ubiquitin-ligase enzyme is important for the specific binding of ubiquitin to its target substrate, which depends on their specific domains [39]. In collaboration with ubiquitin-activating enzyme E1 and ubiquitin-conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of several biologically important protein substrates for targeted degradation via the 26S proteasome, and they engage in nonproteolytic regulation of their functions and subcellular localization.…”