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TDG is a novel tumor suppressor of liver malignancies

Haider M Hassan1,2, Majdina Isovic1,2, Michael Tully Underhill3

  • 1Department of Biochemistry, Western University, London, Ontario, Canada.

Molecular & Cellular Oncology
|September 18, 2020
PubMed

Insights

Loss of thymine DNA glycosylase (TDG) disrupts liver DNA demethylation and bile acid/glucose balance, leading to hepatocellular carcinoma (HCC) in mice. This study reveals TDG

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cancer Research

Background:

  • Thymine DNA glycosylase (TDG) plays a role in DNA repair and demethylation.
  • Dysregulation of bile acid and glucose homeostasis is linked to liver diseases, including cancer.

Purpose of the Study:

  • To investigate the role of TDG in liver homeostasis and hepatocellular carcinoma (HCC) development.
  • To elucidate the molecular mechanisms by which TDG loss contributes to HCC.

Main Methods:

  • Conditional gene deletion of TDG in mouse liver.
  • Analysis of DNA demethylation, bile acid metabolism, and glucose homeostasis.
  • Assessment of HCC development and progression.

Main Results:

  • Conditional deletion of TDG in mice resulted in a late onset of HCC.
  • TDG loss disrupted active DNA demethylation in the liver.
  • FXR-SHP regulatory cascade was dysregulated, leading to loss of bile acid and glucose homeostasis.

Conclusions:

  • TDG is crucial for maintaining liver homeostasis and preventing HCC.
  • Disruption of DNA demethylation and metabolic pathways by TDG loss predisposes to liver cancer.
  • Targeting TDG or related pathways may offer therapeutic strategies for HCC.
Keywords:
FXRSHPThymine DNA Glycosylaseactive DNA demethylationbile acidglucose intolerancehepatocellular carcinomaliver cancerten eleven translocation

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