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
Affiliations
Haider M. Hassan
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
Majdina Isovic
Department of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, Canada
Bart Kolendowski
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
Natasha Bauer-Maison
Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada
Oladapo Onabote
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
Matthew Cecchini
Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada
Aaron Haig
Department of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, Canada
Saman Maleki Vareki
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
T. Michael Underhill
Department of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada
Joseph Torchia
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; Corresponding author
Summary: 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. : TDG is a base excision repair protein that is essential for embryonic development. Hassan et al. show that the conditional deletion of TDG in adult mice causes dysregulation of FXR signaling and a loss of glucose and bile acid homeostasis. This leads to a late-onset development of hepatocellular carcinoma. Keywords: thymine DNA glycosylase, active DNA demethylation, TET, hepatocellular carcinoma, FXR, bile acids, insulin resistance, conditional deletion, hepatoblastoma
