NEDD4L Suppresses Proliferation and Promotes Apoptosis by Ubiquitinating RAC2 Expression and Acts as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma

Neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is an HECT (homologous to E6AP C terminus)-type E3 ubiquitin ligase. As previously documented, bioinformatics analysis revealed <i>NEDD4L</i> is downregulated in clear cell renal cell carcinoma (ccRCC). However, the target substrate regulated by NEDD4L in ccRCC remains unknown. Here, we assessed whether NEDD4L regulates Ras-related C3 botulinum toxin substrate 2 (RAC2) expression in ccRCC. In our study, integrated bioinformatics analysis indicated that low expression of <i>NEDD4L</i> and high expression of <i>RAC2</i> were both associated with poor prognosis of ccRCC, pro-tumorigenic immunity, and multiple tumor-associated pathways. Our data confirmed the hypothesis indicated in the previous studies related to the downregulation of <i>NEDD4L</i> in ccRCC. NEDD4L was identified to target the RAC2 threonine 108-proline motif, and <i>RAC2</i> overexpression rescued <i>NEDD4L</i>-mediated cell apoptosis and inhibition of cell growth and migration. Therefore, RAC2 is a novel and first identified target of NEDD4L in ccRCC, and the aberrant less expression of <i>NEDD4L</i> and consequent <i>RAC2</i> upregulation may contribute to renal carcinogenesis. Our study offers insight into <i>NEDD4L</i> as a potential future therapeutic target for renal cell carcinoma or as a novel prognostic biomarker.