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Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a

Xi Zhang1, Jianguo Wu1, Jonathan Choiniere1

  • 1Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States.

Toxicology and Applied Pharmacology
|May 25, 2016
PubMed

Insights

Arsenic exposure silences the tumor suppressor gene PDK4 in liver cells by promoting repressive histone modifications. This epigenetic silencing, mediated by G9a and Suv39H, contributes to liver cancer development.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Environmental Toxicology

Background:

  • Liver cancer incidence correlates with epigenetic silencing of tumor suppressor genes.
  • Arsenic exposure is a known contributor to epigenetic alterations.
  • Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein involved in the TCA cycle, but its epigenetic regulation by arsenic is unclear.

Purpose of the Study:

  • To elucidate the epigenetic mechanisms by which arsenic controls PDK4 expression.
  • To investigate the role of histone methyltransferases G9a and Suv39H in arsenic-mediated PDK4 silencing.

Main Methods:

  • Utilized G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin (CHA) to assess PDK4 expression.
  • Measured histone H3 lysine 9 (H3K9) di- and tri-methylations (H3K9me2/3) levels.
  • Employed siRNA to knock down G9a in hepatocellular carcinoma (HCC) cells.
  • Exposed mouse liver and hepatocytes to arsenic.

Main Results:

  • Histone methyltransferases G9a and Suv39H contribute to PDK4 silencing via H3K9 methylation.
  • Arsenic exposure decreased PDK4 expression by inducing G9a and increasing H3K9me2/3 levels.
  • Arsenic enhanced H3K9me2/3 enrichment at the PKD4 promoter, counteracting BRD's effect.
  • G9a knockdown and arsenic exposure reduced hepatic PDK4 expression in mice and hepatocytes.

Conclusions:

  • Arsenic exposure silences PDK4 expression in hepatic cells and mouse liver through aberrant repressive histone modifications.
  • The findings suggest a mechanism linking environmental arsenic exposure to liver cancer via epigenetic silencing of PDK4.
Keywords:
ArsenicBRD4770G9aH3K9 methylationPDK4

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