Resumen
Metastasis is the main cause of death for patients suffering gastric cancer. Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critical attributes of metastasis, both of which are regulated tightly by DNA methylation and Wnt/ß-catenin signaling. In this study, we unveiled a novel TET1-FOXO4-ß-catenin signaling cascade, in which TET1 inhibits ß-catenin activity and its nuclear translocation through transactivating FOXO4 expression. TET1 expression can significantly inhibit EMT and stemness properties of gastric cancer cells, while knocking-down endogenous TET1 induces metastasis and enhances self-renewal of CSCs by activating canonical Wnt signaling, which could be fully rescued by modulating FOXO4 expression. Our data also showed that low expression of TET1 or FOXO4 predicts poor survival of gastric cancer patients, suggesting reactivation of TET1 or FOXO4 might be a novel therapeutic approach to prevent gastric cancer metastasis.