Involvement of the DNA Demethylase Thymine DNA Glycosylase in Anticancer Drug Resistance.

Abstract

Anticancer drug resistance remains a significant challenge to the efficacy of cancer treatment, with DNA repair enzymes contributing to this resistance. We hypothesized that thymine DNA glycosylases (TDGs) may be involved in anticancer drug resistance given their dual function of DNA repair and demethylation as well as investigated their possible involvement in the induction of β-catenin in SNUC5 cells resistant to 5-fluorouracil (SNUC5/5-FUR) and oxaliplatin (SNUC5/OXTR). The expression of TDG and phospho-β-catenin increased in both resistant cell types when compared to that in SNUC5 cells. Moreover, knockdown of TDG significantly suppressed phospho-β-catenin expression in both resistant cell types, resulting in enhanced sensitivity to anticancer drugs. TDG binding to the β-catenin promoter was stronger in both resistant cell types than in SNUC5 cells, showing a decreased methylation pattern in the CpG islands of the β-catenin promoter. Furthermore, another DNA demethylase, ten-eleven translocation 1 (TET1), showed the same pattern as TDG in both resistant cell types. Additionally, TDG significantly interacted more with TET1 in both resistant cell types than in SNUC5 cells, enhancing binding to the same locus in the β-catenin promoter. These findings suggest that TDG may be a promising target molecule for overcoming drug resistance in colorectal cancer.