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Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice.

  • Cassano M School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Offner S School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Planet E School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Piersigilli A School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Jang SM School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Henry H Clinical Chemistry Laboratory, Lausanne University Hospital, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • Geuking MB Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
  • Mooser C Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
  • McCoy KD Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
  • Macpherson AJ Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
  • Trono D School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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  • 2017-04-04
Published in:
  • Hepatology (Baltimore, Md.). - 2017
Aging
Animals
Carcinogenesis
Carcinoma, Hepatocellular
Diet, High-Fat
Disease Models, Animal
Epigenomics
Female
Genomic Instability
Liver Neoplasms
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Oxidative Stress
Phenotype
Random Allocation
Repressor Proteins
Risk Assessment
Risk Factors
Tripartite Motif-Containing Protein 28
English Hepatocellular carcinoma (HCC) represents the fifth-most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28hep-/- mice display sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28hep-/- -associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge.


CONCLUSION
This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer-prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017;66:235-251).
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/199
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