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

Kyoung Ah Kang1,2, Mei Jing Piao1,2, Herath Mudiyanselage Maheshika Madhuwanthi Senavirathna2

  • 1Jeju Natural Medicine Research Center, Jeju National University, Jeju 63243, Republic of Korea.

Biomolecules & Therapeutics
|October 14, 2025
PubMed

Insights

Thymine DNA glycosylase (TDG) and TET1 are involved in anticancer drug resistance by affecting beta-catenin. Targeting TDG can enhance drug sensitivity in colorectal cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Anticancer drug resistance is a major hurdle in cancer treatment.
  • DNA repair enzymes contribute to drug resistance.
  • Thymine DNA glycosylase (TDG) has dual roles in DNA repair and demethylation.

Purpose of the Study:

  • To investigate the role of TDG in anticancer drug resistance.
  • To explore the involvement of TDG in beta-catenin induction in resistant colorectal cancer cells.
  • To assess TDG's potential as a therapeutic target.

Main Methods:

  • Comparison of TDG and phospho-beta-catenin expression in drug-sensitive and resistant SNUC5 cells.
  • TDG knockdown experiments to assess its effect on beta-catenin and drug sensitivity.
  • Analysis of TDG binding to the beta-catenin promoter and DNA methylation patterns.
  • Investigation of TDG interaction with ten-eleven translocation 1 (TET1).

Main Results:

  • TDG and phospho-beta-catenin expression were elevated in 5-fluorouracil and oxaliplatin-resistant cells.
  • TDG knockdown reduced phospho-beta-catenin and increased drug sensitivity.
  • TDG exhibited stronger binding to the beta-catenin promoter with decreased methylation in resistant cells.
  • TDG interaction with TET1 was enhanced in resistant cells, promoting beta-catenin promoter binding.

Conclusions:

  • TDG plays a significant role in mediating anticancer drug resistance in colorectal cancer.
  • TDG, in conjunction with TET1, influences beta-catenin expression and promoter methylation.
  • TDG represents a potential therapeutic target for overcoming drug resistance.
Keywords:
Anticancer drug resistanceColorectal cancerDNA demethylaseThymine DNA glycosylaseβ-catenin

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