Abstract

Gastric cancer remains a leading cause of cancer mortality worldwide, largely due to its high metastatic potential driven by epithelial-mesenchymal transition (EMT). Here, we identify Deltex E3 ubiquitin ligase 3L (DTX3L) as a previously unrecognized tumor suppressor in gastric cancer. DTX3L expression is markedly reduced in metastatic and mesenchymal-type gastric cancers and positively correlates with favorable patient prognosis. Functional analyses in cell lines, organoids and animal models demonstrate that DTX3L depletion promotes gastric cancer cell migration, invasion, stem-like properties and metastasis, whereas its overexpression exhibits opposite effects. Mechanistically, DTX3L acts as an E3 ubiquitin ligase that directly interacts with and ubiquitinates SNAI1, a master EMT regulator, leading to its GSK-3β dependent proteasomal degradation. Loss of DTX3L stabilizes SNAI1 and enhances EMT and stem-like phenotypes. Moreover, we uncover that TGF-β1-induced miR-135b-5p downregulates DTX3L, forming a regulatory axis that promotes EMT. Collectively, our findings reveal a novel DTX3L-SNAI1 signaling pathway governing EMT and metastasis in gastric cancer, providing mechanistic insight and suggesting DTX3L as a potential prognostic biomarker and therapeutic target.