ArticleToxicology and applied pharmacology2016
Arsenic silences hepatic PDK4 expression through activation of histone H3K9 methylatransferase G9a.
Article in Toxicology and applied pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Regulation of pyruvate dehydrogenase complex: Dancing to different drums in cancer.International journal of cancer · 2026Review
- The efferocytosis-related genes of SLC26A6, TYRO3, and PDK4 have been identified as predictors of prognosis in hepatocellular carcinoma and are associated with the immune status.International journal of medical sciences · 2026Article
- BRD4770 protects against DOX-induced cardiotoxicity by inhibiting apoptosis and ferroptosis.Science advances · 2025Article
- The Role of Epigenetic Mechanisms in the Treatment of GI Cancers.Current cancer drug targets · 2025Review
- Article
- BRD4770 inhibits vascular smooth muscle cell proliferation via SUV39H2, but not EHMT2 to protect against neointima formation.Human cell · 2023Article
- Histone methylation in pre-cancerous liver diseases and hepatocellular carcinoma: recent overview.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Review
- Molecular mechanisms of environmental exposures and human disease.Nature reviews. Genetics · 2023Review
- Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer.Cancers · 2023Article
- Epigenomic reprogramming in iAs-mediated carcinogenesis.Advances in pharmacology (San Diego, Calif.) · 2023Article
- Identification of Methylation-Regulated Differentially Expressed Genes and Related Pathways in Hepatocellular Carcinoma: A Study Based on TCGA Database and Bioinformatics Analysis.Frontiers in oncology · 2021Article
- Histone H3K9 methylation regulates chronic stress and IL-6-induced colon epithelial permeability and visceral pain.Neurogastroenterology and motility · 2020Article
- H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis.Cell death & disease · 2019Article
- Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis.Liver research (Beijing, China) · 2018Article
- High-mobility-group protein 2 regulated by microRNA-127 and small heterodimer partner modulates pluripotency of mouse embryonic stem cells and liver tumor initiating cells.Hepatology communications · 2017Article
- Pyruvate Dehydrogenase Kinase 4 Deficiency Results in Expedited Cellular Proliferation through E2F1-Mediated Increase of Cyclins.Molecular pharmacology · 2017Article
- New Insights into the Epigenetics of Hepatocellular Carcinoma.BioMed research international · 2017Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
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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.
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