Membrane-associated RING ubiquitin ligase RNF-121 and advancement of cancer

Exploration of E3 ubiquitin ligases as potential therapeutic targets has been ongoing for two to three decades. Various chemicals and drugs have been developed to either upregulate or inhibit the activity of E3 ligases, aiming to mitigate several metabolic diseases. Unconventional and improper maintenance of endoplasmic reticulum-associated degradation (ERAD) can cause endoplasmic reticulum stress, which further leads to several diseases, including cancer. Investigating these endoplasmic reticulum-associated E3 ligase’s role in regulating oncogenic proteins and endoplasmic reticulum stress could reveal novel therapeutic targets for cancer treatment and offer deeper insights into endoplasmic reticulum-associated degradation (ERAD) related disease mechanisms. Really interesting new gene finger protein-121 (RNF-121), a membrane-bound really interesting new gene (RING) E3 ligase located in the endoplasmic reticulum/Golgi membrane, regulates the unfolded protein response (UPR) and degrades misfolded proteins via ubiquitylation. Notably, very few proteins like Pat-3 (β-integrin of C. elegans ‘the worm’ (Caenorhabditis elegans M.), vascular endothelial growth factor receptor 2 (VEGFR2), and voltage-gated sodium-ion channel (VGSC) have been identified as substrates of RNF-121, all of which have implications in tumorigenesis. Furthermore, it was observed that the activity of RNF-121 regulates cellular niches in cancer by affecting the apoptosis pathway in breast cancer cell lines. However, the full extent of its role in regulating oncogenic proteins and endoplasmic reticulum-specific stress regulators remains to be explored. Identifying the potential substrates of RNF-121 and understanding the degradation mechanisms could shed light on its broader functions and role in cancer progression and endoplasmic reticulum-stress regulation.