Oncogenic E3 ubiquitin ligase NEDD4 binds to KLF8 and regulates the microRNA-132/NRF2 axis in bladder cancer
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The neuronally expressed developmentally downregulated 4 (NEDD4) gene encodes a ubiquitin ligase that targets the epithelial sodium channel for degradation and has been implicated in tumor growth in various cancers. Hence, in this study, we intended to characterize the functional relevance of the NEDD4-mediated Kruppel-like factor 8/microRNA-132/nuclear factor E2-related factor 2 (KLF8/miR-132/NRF2) axis in the development of bladder cancer. NEDD4 and KLF8 were overexpressed in bladder cancer tissues and were associated with poorer patient survival rates. In bladder cancer cells, NEDD4 intensified the stability and transcriptional activity of KLF8 through ubiquitination to augment cell viability and migratory ability. Our investigations revealed that NEDD4 promotes the binding of KLF8 to the miR-132 promoter region and inhibits the expression of miR-132. KLF8 inhibited the expression of miR-132 to augment the viability and migratory ability of bladder cancer cells. Furthermore, miR-132 downregulated the expression of NRF2 to restrict the viability and migratory ability of bladder cancer cells. In addition, in vivo findings verified that NEDD4 regulates the KLF8/miR-132/NRF2 axis by accelerating tumor growth and lung metastasis. In conclusion, this study highlights NEDD4 as a potential therapeutic target against tumor recurrence and metastasis in bladder cancer.
Abstract
The neuronally expressed developmentally downregulated 4 (NEDD4) gene encodes a ubiquitin ligase that targets the epithelial sodium channel for degradation and has been implicated in tumor growth in various cancers. Hence, in this study, we intended to characterize the functional relevance of the NEDD4-mediated Kruppel-like factor 8/microRNA-132/nuclear factor E2-related factor 2 (KLF8/miR-132/NRF2) axis in the development of bladder cancer. NEDD4 and KLF8 were overexpressed in bladder cancer tissues and were associated with poorer patient survival rates. In bladder cancer cells, NEDD4 intensified the stability and transcriptional activity of KLF8 through ubiquitination to augment cell viability and migratory ability. Our investigations revealed that NEDD4 promotes the binding of KLF8 to the miR-132 promoter region and inhibits the expression of miR-132. KLF8 inhibited the expression of miR-132 to augment the viability and migratory ability of bladder cancer cells. Furthermore, miR-132 downregulated the expression of NRF2 to restrict the viability and migratory ability of bladder cancer cells. In addition, in vivo findings verified that NEDD4 regulates the KLF8/miR-132/NRF2 axis by accelerating tumor growth and lung metastasis. In conclusion, this study highlights NEDD4 as a potential therapeutic target against tumor recurrence and metastasis in bladder cancer.
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