The multifaceted role of E3 ubiquitin ligases in cancer metastasis: mechanisms, targets, and therapeutic implications

Cancer metastasis is one of the hallmarks of cancer. This multistep process involves a cascade of alterations at the cellular and molecular level, including the epithelial-to-mesenchymal transition (EMT), invasion, migration, extracellular matrix (ECM) degradation, angiogenesis, and colonization. Expression level of critical factors associated with these processes is altered at the post-translational level through ubiquitination. Therefore, E3 ubiquitin ligases, components of the ubiquitin-mediated proteasome system, play a crucial role in controlling each step of metastasis by promoting the ubiquitination of several important factors. In this review, we have summarized the importance of E3 ligase in metastasis. Several E3 ligases act as promoters, while others act as repressors of metastasis. This article focuses on the potential role of E3 ubiquitin ligases in cancer metastasis and reveals their molecular function and targets, which are crucial for therapeutic interventions in anti-cancer therapies. Further, we covered the development of small molecule inhibitors and proteolysis-targeting chimeras to target E3 ubiquitin ligases involved in promoting metastasis for therapeutic intervention. Despite tremendous advancements, there are still many unanswered questions, especially regarding the complete characterization of the diverse range of E3 ligase functions and the conversion of preclinical discoveries into successful clinical treatments. In addition, future directions are concentrated on using technologies to develop highly specific therapeutic interventions and exploring their potential in combination with other treatment modalities, including immunotherapy, to ultimately overcome the challenges of cancer metastasis.