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 NEDD4L 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 NEDD4L and high expression of RAC2 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 NEDD4L in ccRCC. NEDD4L was identified to target the RAC2 threonine 108-proline motif, and RAC2 overexpression rescued NEDD4L-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 NEDD4L and consequent RAC2 upregulation may contribute to renal carcinogenesis. Our study offers insight into NEDD4L as a potential future therapeutic target for renal cell carcinoma or as a novel prognostic biomarker.