DTX3 suppresses bladder cancer cell invasion and metastasis by inhibiting the Notch signaling pathway.

Deltex E3 ubiquitin ligase 3 (DTX3) was identified as a tumor suppressor in human cancers. However, whether DTX3 could suppress the progression of bladder cancer (BC) remains unknown. In this study, DTX3 downregulation in BC tissues was confirmed at mRNA and protein levels, and decreased DTX3 expression was associated with poor prognosis. DTX3 knockdown triggered aberrant epithelial-to-mesenchymal transition (EMT), principally via downregulation of E-cadherin and upregulation of N-cadherin, MMP9, Snail, and Slug. Gain- and loss-of-function assays indicated that DTX3 acted as a suppressor gene by inhibiting the migration and invasion of BC cells both in vivo and in vitro. Further analysis revealed that DTX3 inhibited Notch signaling pathway activity, and the Notch signaling inhibitor DAPT could partially reverse the effects of DTX3 knockdown on the metastatic abilities of BC cells. Mechanically, DTX3 bind to Notch intracellular domain (NICD) via its C-terminal RING finger domain (RFD), ubiquitinated, and degraded NICD, resulting in repression of the Notch pathway. Our findings reveal the key role of DTX3 in binding to NICD, promoting its ubiquitination and protein degradation, and suppressing the activation of the Notch signaling pathway to inhibit BC invasion and metastasis.