Nickel-Induced Histone Hypoacetylation: The Role of Reactive Oxygen Species

Kang, Jiuhong; Zhang, Y.; Chen, J.; Chen, H.; Lin, Changjun; Wang, Q.; Ou, Yingxian

doi:10.1093/toxsci/kfg137

Cited by 96 publications

(63 citation statements)

References 22 publications

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“…In animal experiments, injection of particulate nickel compounds (nickel sulfide or nickel subsulfide) into mice induced formation of malignant fibrous histiocytomas and sarcomas, with the p16 and Fhit genes often found to be epigenetically silenced in these cancers (9,10). Additional studies have demonstrated that nickel exposure caused truncation of histone H2B and H2A as well as global alterations of a variety of histone modifications, such as histone acetylation, methylation, phosphorylation, and ubiquitination (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the underlying mechanisms responsible for these nickel-induced epigenetic alterations are poorly understood.…”

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confidence: 99%

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Chen

Giri

Zhang

et al. 2010

Journal of Biological Chemistry

134

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Iron-and 2-oxoglutarate-dependent dioxygenases are a diverse family of non-heme iron enzymes that catalyze various important oxidations in cells. A key structural motif of these dioxygenases is a facial triad of 2-histidines-1-carboxylate that coordinates the Fe(II) at the catalytic site. Using histone demethylase JMJD1A and DNA repair enzyme ABH2 as examples, we show that this family of dioxygenases is highly sensitive to inhibition by carcinogenic nickel ions. We find that, with iron, the 50% inhibitory concentrations of nickel (IC 50 Nickel compounds are human respiratory carcinogens (1), causing a very high incidence of lung and nasal cancers in nickel refinery workers (2). Over 20 years ago, our group reported that cells phagocytosed particulate nickel compounds, and the dissolution of these particles inside of the cells generated high concentrations of free nickel ions in the cytoplasm and nucleus (3). Using a dye that fluoresces when intracellular nickel ion binds to it, we showed that both soluble and insoluble nickel compounds were able to elevate the levels of nickel ions in the cytoplasmic and nuclear compartments (4). A strong correlation was found between the uptake of particulate nickel compounds by cells and subsequent cell transformation (5), suggesting that intracellular nickel ion concentration is a major determinant of toxicity and carcinogenicity of nickel compounds. Identifying the intracellular targets of nickel ions is therefore crucial to understand the underlying mechanism for the carcinogenic effects of nickel compounds.Silencing of tumor suppressor gene(s) by epigenetic mechanisms represents one of the potential mechanisms of nickel carcinogenesis. Epigenetic events, which include DNA methylation and histone modifications, are ubiquitously involved in the regulation of gene expression. By using a transgenic cell model with the target gene placed near heterochromatin, we were the first to demonstrate that nickel exposure caused a very high frequency of transgene silencing by increasing DNA methylation and repressive histone marks at the promoter of the silenced transgene (6 -8). In animal experiments, injection of particulate nickel compounds (nickel sulfide or nickel subsulfide) into mice induced formation of malignant fibrous histiocytomas and sarcomas, with the p16 and Fhit genes often found to be epigenetically silenced in these cancers (9,10). Additional studies have demonstrated that nickel exposure caused truncation of histone H2B and H2A as well as global alterations of a variety of histone modifications, such as histone acetylation, methylation, phosphorylation, and ubiquitination (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the underlying mechanisms responsible for these nickel-induced epigenetic alterations are poorly understood. In our recent study, we reported that nickel increases the global levels of mono-and di-methylated histone H3 lysine 9 (H3K9me1 and H3K9me2) not by affecting histone methyltransferases but rather by inhibiting a group of unidentified iron-and...

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confidence: 99%

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Chen

Giri

Zhang

et al. 2010

Journal of Biological Chemistry

134

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“…The diverse pharmacological activities of curcumin have been attributed to its actions on multiple cellular targets. In addition to cyclooxygenase, cytochrome P450, glutathione Stransferase, protein kinase C, and telomerase (9,19,41), curcumin can also inhibit HATs and HDACs (4,26), thereby affecting the status of histone acetylation (16,18,(20)(21)(22)35). In these cases, histone hypoacetylation occurs on both H3 and H4.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Effect of Curcumin on Malaria Parasite Plasmodium falciparum : Inhibition of Histone Acetylation and Generation of Reactive Oxygen Species

Cui

Miao

Cui

2007

Antimicrob Agents Chemother

222

168

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The emergence of multidrug-resistant parasites is a major concern for malaria control, and development of novel drugs is a high priority. Curcumin, a natural polyphenolic compound, possesses diverse pharmacological properties. Among its antiprotozoan activities, curcumin was potent against both chloroquine-sensitive and -resistant Plasmodium falciparum strains. Consistent with findings in mammalian cell lines, curcumin's prooxidant activity promoted the production in P. falciparum of reactive oxygen species (ROS), whose cytotoxic effect could be antagonized by coincubation with antioxidants and ROS scavengers. Curcumin treatment also resulted in damage of both mitochondrial and nuclear DNA, probably due to the elevation of intracellular ROS. Furthermore, we have demonstrated that curcumin inhibited the histone acetyltransferase (HAT) activity of the recombinant P. falciparum general control nonderepressed 5 (PfGCN5) in vitro and reduced nuclear HAT activity of the parasite in culture. Curcumin-induced hypoacetylation of histone H3 at K9 and K14, but not H4 at K5, K8, K12, and K16, suggested that curcumin caused specific inhibition of the PfGCN5 HAT. Taken together, these results indicated that at least the generation of ROS and down-regulation of PfGCN5 HAT activity accounted for curcumin's cytotoxicity for malaria parasites.

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“…This notion is in agreement with the observations that there was a time lag between the elevation of global H3K9 dimethylation and the increase in the frequency of the gpt Ϫ phenotype following nickel ion exposure, as well as the observation that the gpt Ϫ phenotype was readily reversed by 5-aza-2Ј-deoxycytidine treatment. Additional histone modifications were altered following nickel ion exposure, such as a striking decrease of both histone acetylation (15,20) and H3K4 dimethylation (Fig. 7b), which may act in concert to repress the expression of the gpt transgene.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, insoluble nickel compounds were found to decrease the global level of histone H4 acetylation in both yeast and mammalian cells (3). Recently, two independent groups reported that exposure to nickel ions also decreased global histone acetylation in mammalian cells (15,20).…”

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Nickel Ions Increase Histone H3 Lysine 9 Dimethylation and Induce Transgene Silencing

Chen

Kluz

et al. 2006

Molecular and Cellular Biology

211

186

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We have previously reported that carcinogenic nickel compounds decreased global histone H4 acetylation and silenced the gpt transgene in G12 Chinese hamster cells. However, the nature of this silencing is still not clear. Here, we report that nickel ion exposure increases global H3K9 mono-and dimethylation, both of which are critical marks for DNA methylation and long-term gene silencing. In contrast to the up-regulation of global H3K9 dimethylation, nickel ions decreased the expression and activity of histone H3K9 specific methyltransferase G9a. Further investigation demonstrated that nickel ions interfered with the removal of histone methylation in vivo and directly decreased the activity of a Fe(II)-2-oxoglutarate-dependent histone H3K9 demethylase in nuclear extract in vitro. These results are the first to show a histone H3K9 demethylase activity dependent on both iron and 2-oxoglutarate. Exposure to nickel ions also increased H3K9 dimethylation at the gpt locus in G12 cells and repressed the expression of the gpt transgene. An extended nickel ion exposure led to increased frequency of the gpt transgene silencing, which was readily reversed by treatment with DNAdemethylating agent 5-aza-2-deoxycytidine. Collectively, our data strongly indicate that nickel ions induce transgene silencing by increasing histone H3K9 dimethylation, and this effect is mediated by the inhibition of H3K9 demethylation.Posttranslational modifications of histone N-terminal tails are important in chromatin organization, gene transcription, and DNA replication and repair (19). To date, a diverse array of histone modifications has been identified, including acetylation, methylation, phosphorylation, and ubiquitination (28). Among them, methylation of histone H3 lysine 9 (H3K9) is one of the best-studied modifications. H3K9 may be mono-, di-, or trimethylated without changing the positive charge of the lysine residue. Trimethylated H3K9 is typically connected with constitutive heterochromatin, while mono-and dimethylated H3K9 are mainly located in euchromatin and generally linked to repressed promoter regions (29). Suv39h family enzymes are responsible for trimethylation of H3K9 in vivo (27,29), while G9a and GLP/EuHMTase 1 are two major histone methyltransferases responsible for H3K9 dimethylation in vivo (35,36). Genetic ablation of either G9a or GLP/EuHMTase 1 dramatically diminished global H3K9 dimethylation in mouse embryonic stem cells (35,36).Methylation of histone lysines had long been thought of as a "permanent" modification since there was no known enzyme to demethylate. However, this dogma was challenged by the recent discoveries of histone H3 lysine 4 (H3K4) demethylase LSD1 and H3 lysine 36 (H3K36) demethylase JHDM1 (JmjC domain-containing histone demethylase 1) (32, 39). Although both LSD1 and JHDM1 can remove the methyl group from lysine residues on histone H3, they utilize different mechanisms to demethylate. LSD1 is a flavin-dependent amine oxidase and removes the methyl group from mono-or dimethyl H3K4 by catalyzing the...

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Nickel-Induced Histone Hypoacetylation: The Role of Reactive Oxygen Species

Cited by 96 publications

References 22 publications

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Cytotoxic Effect of Curcumin on Malaria Parasite Plasmodium falciparum : Inhibition of Histone Acetylation and Generation of Reactive Oxygen Species

Nickel Ions Increase Histone H3 Lysine 9 Dimethylation and Induce Transgene Silencing

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