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Targeting Wnt/β-catenin signaling by TET1/FOXO4 inhibits metastatic spreading and self-renewal of cancer stem cells in gastric cancer

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Item Type:Article
Title:Targeting Wnt/β-catenin signaling by TET1/FOXO4 inhibits metastatic spreading and self-renewal of cancer stem cells in gastric cancer
Creators Name:Qi, J., Cui, D., Wu, Q.N., Zhao, Q., Chen, Z.H., Li, L., Birchmeier, W., Yu, Y. and Tao, R.
Abstract: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/β-catenin signaling. Here, we studied the functions of DNA dioxygenase TET1 in regulating Wnt signaling and in gastric cancer metastasis. Knocking-down and overexpressing TET1 in gastric cancer cells promoted and inhibited metastatic spreading to the liver in immune-deficient mice, respectively. TET1 showed inhibitory effects on metastasis-related features -EMT and CSC, which were reversed by interfering with Wnt/β-catenin signaling. RNA-sequencing identified FOXO4 as a direct transactivating target of TET1. FOXO4 directly interacted with β-catenin and recruited it in the cytoplasm, so as to inhibit β-catenin-mediated transcription of Wnt target genes, including CSC marker EpCAM. Moreover, modulation of FOXO4 could reverse the effects of TET1 manipulation on EMT and self-renewal of CSCs. The analysis with clinical samples confirmed the value of FOXO4 as an independent prognostic predictor of patients' overall survival. Taken together, regulation of Wnt signaling by TET1/FOXO4 is essential for metastasis-associated cellular properties, and targeting TET1/FOXO4/β-catenin pathway may serve as promising therapeutics in the prevention and treatment of gastric cancer metastasis.
Keywords:Gastric Cancer, TET1, FOXO4, Wnt Signaling, Cancer Stem Cell, Metastasis, Animals, Mice
Source:Cancers
ISSN:2072-6694
Publisher:MDPI
Volume:14
Number:13
Page Range:3232
Date:30 June 2022
Official Publication:https://doi.org/10.3390/cancers14133232
PubMed:View item in PubMed

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