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Arsenic silences liver PDK4 expression through activation of histone H3K9 methylatransferase G9a
Author(s) -
Zhang Xi,
Choiniere Jonathan,
Bennett Jason,
Wang Li
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1193.5
Subject(s) - pdk4 , gene silencing , histone h3 , histone , chemistry , epigenetics , cancer research , microbiology and biotechnology , biology , downregulation and upregulation , biochemistry , gene
It is well established that the increased liver cancer incidence is strongly associated with epigenetic silencing of tumor suppressor genes; the latter is contributed by the environmental exposure to arsenic. The pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein that regulates TCA cycle. However, little is known about its role in arsenic‐mediated tumor progression. In the present study, we show that the inactivation of PDK4 in hepatocellular carcinoma (HCC) cells is resulted from aberrant repressive histone modification. Histone methyltrasferase G9a‐ and Suv39H‐mediated histone H3 lysine 9 (H3K9) methylations contribute to the PDK4 silencing in HCC cells. The PDK4 expression is induced by G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin. In contrast, arsenic exposure increases G9a protein expression and the global levels of H3K9 di‐ and tri‐methylations (H3K9me2/3). Compared to BRD treated cells, arsenic exposure restores the decreased H3K9me2/3 enrichment in the PKD4 promoter. Our results also show that the PDK4 expression is refractory to BRD‐mediated transcriptional activation upon arsenic exposure. When C57Bl/6 mice receive arsenic in drinking water alone or in combination with BRD treatment, the hepatic expression of PDK4 is induced by BRD which is markedly reversed by arsenic. Based on these observations, we conclude that arsenic disrupts the epigenetic restoration of PDK4 expression in both HCC cells and in mouse liver. Support or Funding Information NIEHS 1R01ES025909