Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma
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). TD...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720303533 |
| _version_ | 1819138680463294464 |
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| author | Haider M. Hassan Majdina Isovic Bart Kolendowski Natasha Bauer-Maison Oladapo Onabote Matthew Cecchini Aaron Haig Saman Maleki Vareki T. Michael Underhill Joseph Torchia |
| author_facet | Haider M. Hassan Majdina Isovic Bart Kolendowski Natasha Bauer-Maison Oladapo Onabote Matthew Cecchini Aaron Haig Saman Maleki Vareki T. Michael Underhill Joseph Torchia |
| author_sort | Haider M. Hassan |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-22T11:10:37Z |
| format | Article |
| id | doaj.art-1c7f0c81c5be4026bcbfcb150146cc95 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T11:10:37Z |
| publishDate | 2020-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1c7f0c81c5be4026bcbfcb150146cc952022-12-21T18:28:09ZengElsevierCell Reports2211-12472020-04-01311Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular CarcinomaHaider M. Hassan0Majdina Isovic1Bart Kolendowski2Natasha Bauer-Maison3Oladapo Onabote4Matthew Cecchini5Aaron Haig6Saman Maleki Vareki7T. Michael Underhill8Joseph Torchia9Department 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, CanadaDepartment of Oncology, The London Regional Cancer Program, London, ON, Canada; Lawson Health Research Institute, London Health Science Centre, London, ON, CanadaDepartment 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, CanadaDepartment of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, CanadaDepartment 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, CanadaDepartment of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, CanadaDepartment of Pathology and Laboratory Medicine, London Health Science Centre, London, ON, CanadaDepartment 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, CanadaDepartment of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC, CanadaDepartment 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 authorSummary: 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, hepatoblastomahttp://www.sciencedirect.com/science/article/pii/S2211124720303533 |
| spellingShingle | Haider M. Hassan Majdina Isovic Bart Kolendowski Natasha Bauer-Maison Oladapo Onabote Matthew Cecchini Aaron Haig Saman Maleki Vareki T. Michael Underhill Joseph Torchia Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma Cell Reports |
| title | Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma |
| title_full | Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma |
| title_fullStr | Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma |
| title_full_unstemmed | Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma |
| title_short | Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma |
| title_sort | loss of thymine dna glycosylase causes dysregulation of bile acid homeostasis and hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720303533 |
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