Comprehensive analysis of the role of NEDD4 in pan-cancer and experimental verification of its role in KIRC progression

Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) serves as the founding member of the HECT ubiquitin ligase family involved in protein degradation within the ubiquitin-proteasome system. Although numerous studies have demonstrated the involvement of NEDD4 in carcinogenesis by regulating the ubiquitylation-mediated turnover of different substrates, there is still a lack of pan-cancer studies investigating its relevance across various types of cancers. In this study, we aimed to conduct a comprehensive pan-cancer analysis of NEDD4 and elucidate its role in tumorigenesis Firstly, the results of our study unveiled that NEDD4 was dysregulated in a variety of tumors including Kidney Renal Clear Cell Carcinoma (KIRC). Survival analysis revealed that the dysregulation of NEDD4 expression was associated with the patient prognosis. Additionally, immunoassays indicated that NEDD4 might be associated with the expression of multiple tumor immune checkpoints. Finally, we further analyzed NEDD4 in KIRC and found that NEDD4 may regulate KIRC apoptosis by regulating PI3K-AKT signaling. Cell experiments confirmed that the knockdown of NEDD4 promoted the proliferation, invasion, and migration of A498 cells. Furthermore, PTEN, a negative regulator of PI3K-AKT signaling, was found to be regulated by NEDD4. In conclusion, the results of this study suggest that NEDD4 is a potential tumor prognostic biomarker and immunotherapeutic target.