N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation.

The molecular mechanisms driving metastatic progression in breast cancer patients remain poorly understood. Here, we identified N4BP3 as a new regulator in promoting breast cancer metastasis. N4BP3 is enriched in breast tumor tissue and negatively correlates with clinical outcomes in breast cancer patients. The results show that N4BP3 plays a crucial role in regulating breast cancer cell invasion in vitro, and N4BP3 depletion suppresses metastases formation in vivo. N4BP3 alters the expression of epithelial-mesenchymal transition markers and specifically targets E-cadherin in breast cancer cells. Intriguingly, we identified a novel E3 ligase NEDD4 for E-cadherin, and further revealed that N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation. Together, this study uncovers an unprecedented role for N4BP3 in breast cancer metastasis and elucidates the underlying molecular mechanisms.