DTX3L Inhibits the EMT, Metastasis, and Stem‐Like Features of Gastric Cancer Through Promoting GSK‐3β Dependent SNAI1 Decay

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.