title: Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a.
abstract: It is well established that increased liver cancer incidence is strongly associated with epigenetic silencing of tumor suppressor genes; the latter is contributed by the environmental exposure to arsenic. Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial protein that regulates the TCA cycle. However, the epigenetic mechanisms mediated by arsenic to control PDK4 expression remain elusive. In the present study, we showed that histone methyltransferase G9a- and Suv39H-mediated histone H3 lysine 9 (H3K9) methylations contributed to PDK4 silencing in hepatic cells. The PDK4 expression was induced by G9a inhibitor BRD4770 (BRD) and Suv39H inhibitor Chaetocin (CHA). In contrast, arsenic exposure decreased PDK4 expression by inducing G9a and increasing H3K9 di- and tri-methylations levels (H3K9me2/3). In addition, arsenic exposure antagonizes the effect of BRD by enhancing the enrichment of H3K9me2/3 in the PKD4 promoter. Moreover, knockdown of G9a using siRNA induced PDK4 expression in HCC cells. Furthermore, arsenic decreased hepatic PDK4 expression as well as diminished the induction of PDK4 by BRD in mouse liver and hepatocytes. Overall, the results suggest that arsenic causes aberrant repressive histone modification to silence PDK4 in both HCC cells and in mouse liver.
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Choiniere
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States; Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, United States.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT 062696, United States; Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, United States; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06520, United States. Electronic address: li.wang@uconn.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology; D011494:Protein Kinases / Q000096:biosynthesis*; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C586537:BRD4770; D001549:Benzamides; D001562:Benzimidazoles; D006657:Histones; D010879:Piperazines; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C002511:chaetocin; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D001151:Arsenic
keywords: Arsenic; BRD4770; G9a; H3K9 methylation; PDK4