Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma

Haider M Hassan; Majdina Isovic; Bart Kolendowski; Natasha Bauer-Maison; Oladapo Onabote; Matthew Cecchini; Aaron Haig; Saman Maleki Vareki; T Michael Underhill; Joseph Torchia

doi:10.1016/j.celrep.2020.03.039

Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma

Cell Rep. 2020 Apr 7;31(1):107475. doi: 10.1016/j.celrep.2020.03.039.

Affiliations

¹ Department of Biochemistry, Western University, London, ON, Canada; Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.
² Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada.
³ Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada.
⁴ Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada; Department of Interdisciplinary Medical Sciences, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada.
⁵ Department of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.
⁶ Department of Biochemistry, Western University, London, ON, Canada; Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada. Electronic address: jtorchia@uwo.ca.

PMID: 32268085
DOI: 10.1016/j.celrep.2020.03.039

Abstract

Thymine DNA glycosylase (TDG) is a nuclear receptor coactivator that plays an essential role in the maintenance of epigenetic stability in cells. Here, we demonstrate that the conditional deletion of TDG in adult mice results in a male-predominant onset of hepatocellular carcinoma (HCC). TDG loss leads to a prediabetic state, as well as bile acid (BA) accumulation in the liver and serum of male mice. Consistent with these data, TDG deletion led to dysregulation of the farnesoid X receptor (FXR) and small heterodimer partner (SHP) regulatory cascade in the liver. FXR and SHP are tumor suppressors of HCC and play an essential role in BA and glucose homeostasis. These results indicate that TDG functions as a tumor suppressor of HCC by regulating a transcriptional program that protects against the development of glucose intolerance and BA accumulation in the liver.

Keywords: FXR; TET; active DNA demethylation; bile acids; conditional deletion; hepatoblastoma; hepatocellular carcinoma; insulin resistance; thymine DNA glycosylase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Acids and Salts / genetics
Bile Acids and Salts / metabolism*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / physiopathology*
Female
Glucose / metabolism
Hep G2 Cells
Homeostasis
Humans
Liver / pathology
Liver Neoplasms / metabolism
Liver Neoplasms / physiopathology
Male
Mice
Mice, Inbred C57BL
Receptors, Cytoplasmic and Nuclear / metabolism
Thymine DNA Glycosylase / metabolism*
Thymine DNA Glycosylase / physiology

Substances

Bile Acids and Salts
Receptors, Cytoplasmic and Nuclear
nuclear receptor subfamily 0, group B, member 2
farnesoid X-activated receptor
Thymine DNA Glycosylase
Glucose

Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma

Authors

Affiliations

Abstract

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MeSH terms

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