Unraveling the Complex Web of Mechanistic Regulation of Versatile NEDD4 Family by Non-Coding RNAs in Carcinogenesis and Metastasis: From Cell Culture Studies to Animal Models.

Discoveries related to an intriguing feature of ubiquitination have prompted a detailed analysis of the ubiquitination patterns in malignant cells. How the "ubiquitinome" is reshaped during multistage carcinogenesis has garnered significant attention. Seminal studies related to the structural and functional characterization of NEDD4 (Neuronal precursor cell-expressed developmentally downregulated-4) have consolidated our understanding at a new level of maturity. Additionally, regulatory roles of non-coding RNAs have further complicated the complex interplay between non-coding RNAs and the members of NEDD4 family. These mechanisms range from the miRNA-mediated targeting of NEDD4 family members to the regulation of transcriptional factors for a broader range of non-coding RNAs. Additionally, the NEDD4-mediated degradation of different proteins is modulated by lncRNAs and circRNAs. The miRNA-mediated targeting of NEDD4 family members is also regulated by circRNAs. Tremendous advancements have been made in the identification of different substrates of NEDD4 family and in the comprehensive analysis of the molecular mechanisms by which various members of NEDD4 family catalyze the ubiquitination of substrates. In this review, we have attempted to summarize the multifunctional roles of the NEDD4 family in cancer biology, and how different non-coding RNAs modulate these NEDD4 family members in the regulation of cancer. Future molecular studies should focus on the investigation of a broader drug design space and expand the scope of accessible targets for the inhibition/prevention of metastasis.