TET1-Mediated Tumor Inhibition and Dox Resistance in Colon Cancer by Blocking WNT / β-Catenin Pathway

Abstract BackgroundAs DNA demethylation protein, Ten-eleven translocation 1 (TET1) has been widely reported that is related to tumorigenesis and tumor metastasis. This study is to investigate the role and regulation mechanism of TET1 in colon cancer.Methods The TET1 and Catenin beta-1 (CTNNB1) expression level in colon cancer samples and cancer cell lines HCT116/SW480 were observed to discover the relationship between these two genes. Knockdown and overexpression of TET1 through shRNA and CRISPR technology were used to elucidate the effect of TET1 on WNT/β-catenin pathway. The 5-hmC/5-mC level were explored by bisulfate sequencing (BSP) and Chromatin immunoprecipitation (ChIP) to further explain the regulation mechanism. Combined with the reverse assay and transwell invasion assay, the cell migration and invasion ability were tested. Finally, the role of TET1 on DOX resistance was analyzed.Results TET1 downregulated in colon cancer and showed an opposite expression trend with WNT pathway associated gene CTNNB1. TET1 bound to CTNNB1 promotor and catalyzed demethylation to activate transcription of CTNNB1, inhibiting WNT/β‐catenin signaling pathways. Colon cancer cells proliferation was promoted by TET1 downregulation, which was further verified as shTET1 could upregulate the tumor invasion. The DOX addition could rescue the cell migration, compared with normal expression of TET1. Meanwhile, TET1 down-regulation was related to DOX resistances.Conclusion TET1 played as a DNA hydroxymethylation activates inhibitors of the WNT/β-catenin signaling pathway in colon tumor and TET1 down-regulation contributed to DOX-resistance, which might provide reference to targeting therapy in clinical practice.