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TET1 is a tumour suppressor that inhibits bladder cancer progression

ABSTRACT: Ten-Eleven Translocation 1 (TET1) is a member of methylcytosine dioxygenase, which catalyse 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) that promote the demethylation process. The diminished expression of TET1 protein and 5-hmC in many tumors indicate a critical role for the maintenance of cell stability. However, role of TET1 in bladder cancer development remains unclear. Here we found that TET1 expression was downregulated in bladder cancer tissues compared with normal urothelium and was inversely related to patient overall survival. TET1 silencing in bladder cancer cells increase proliferation and inhibited cell migration and invasion while its re-expression inhibits their proliferation and the growth of tumor xenografts. Furthermore, we found that TET1 binds to the promoter of the TSG to maintain its hypomethylated which interacts with β-catenin and suppress its nuclear translocation, thus inhibiting β-catenin transcriptional activity and downstream genes. In conclusion, TET1 acts as a tumor suppressor gene in bladder cancer cells by suppressing β-catenin signaling. This study may facilitate efforts to therapeutic strategy for patients with bladder cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137646 | GEO | 2020/06/16

REPOSITORIES: GEO

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Project description:DNA methylation is a heritable epigenetic modification involved in gene silencing, imprinting, and the suppression of retrotransposons. Global DNA demethylation occurs in the early embryo and the germline and may be mediated by Tet (ten-eleven-translocation) enzymes, which convert 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC). Tet enzymes have been extensively studied in mouse embryonic stem (ES) cells, which are generally cultured in the absence of Vitamin C, a potential co-factor for Fe(II) 2-oxoglutarate dioxygenase enzymes like Tets. Here we report that addition of Vitamin C to ES cells promotes Tet activity leading to a rapid and global increase in hmC. This is followed by DNA demethylation of numerous gene promoters and up-regulation of demethylated germline genes. Tet1 binding is enriched near the transcription start site (TSS) of genes affected by Vitamin C treatment. Importantly, Vitamin C, but not other antioxidants, enhances the activity of recombinant human Tet1 in a biochemical assay and the Vitamin C-induced changes in hmC and mC are entirely suppressed in Tet1/2 double knockout (Tet DKO) ES cells. Vitamin C has the strongest effects on regions that gain methylation in cultured ES cells compared to blastocysts and in vivo are methylated only after implantation. In contrast, imprinted regions and intracisternal A-particle (IAP) elements, which are resistant to demethylation in the early embryo, are resistant to Vitamin C-induced DNA demethylation. Collectively, this study establishes that Vitamin C is a direct regulator of Tet activity and DNA methylation fidelity in ES cells. Oct4-GiP mouse embryonic stem (ES) cells were cultured in the presence or absence of Vitamin C (L-ascorbic acid 2-phosphate, 100 M-NM-<g/ml) for 12 or 72 hours. Cells were maintained in N2B27 medium supplemented with LIF (1000 U/ml), MEK inhibitor PD0325901 (1 M-NM-<M), and GSK3M-NM-2 inhibitor CHIR99021 (3 M-NM-<M). Genomic DNA was used for DNA immunoprecipitation with antibodies against 5-hydroxymethylcytosine (hmC) or 5-methylcytosine (mC). Immunoprecipitated DNA was adaptor-ligated for paired-end sequencing on an Illumina HiSeq and sequence reads were aligned to the mm9 mouse reference genome for analysis.