GATA6 regulates epithelial-mesenchymal transition and metastasis through regulating MUC1/β-catenin pathway in cholangiocarcinoma
Background: GATA6 can act as an oncogene or tumour suppressor in different cancers. Previously, we found that aberrant expression of GATA6 promotes metastasis in cholangiocarcinoma (CCA). However, the mechanism is unclear. Methods: Ninety-one CCA samples were collected. Immunohistochemistry, knockdown and overexpression by lentivirus transfection, luciferase reporter assays, ChIP-sequencing and protein-immunoprecipitation (IP) assays were performed. Results: GATA6 expression was positively
... was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. GATA6 promoted epithelial-mesenchymal transition (EMT) in CCA cells in vitro and in vivo . ChIP sequencing analysis screened MUC1 as a new target of GATA6. GATA6 upregulated MUC1 transcription through binding 1584 and 1456 GATA-motifs. MUC1 promoted EMT in CCA cells. MUC1 knockdown significantly abrogated GATA6-induced EMT in CCA cells. β-Catenin is an important transcriptional coactivator in regulating EMT. MUC1 expression was significantly associated with β-catenin nuclear expression in 91 CCA samples. MUC1 upregulated β-catenin nuclear expression in CCA cells. Moreover, MUC1 interacted with β-catenin in CCA cells. MUC1 knockdown significantly decreased the binding of MUC1 and β-catenin. The data indicated that MUC1 regulated EMT through interacting with β-catenin and upregulating its nuclear expression in CCA cells. Conclusion: GATA6 regulates EMT through the MUC1/β-catenin pathway in CCA, with potential implications for anti-metastatic therapy.