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

SIMPLE SUMMARY: Cancer progression eventually may lead to metastasis, which is responsible for at least 90% cancer-related deaths. The epithelial-to-mesenchymal transition plays a critical role in promoting metastasis and is considered a new target in anticancer drug discovery. The E3 ubiquitin-ligases responsible for targeted protein degradation emerge as molecularly defined targets involved in epithelial-to-mesenchymal transition. This review highlights the novel E3 ubiquitin-ligases responsible for targeted protein degradation involved in epithelial-to-mesenchymal transition, a field that promises to be one of the greatest innovation in small-molecule drug discovery. 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.