Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway

Ke, Qingdong; Li, Qin; Ellen, Thomas P.; Sun, Hong; Costa, Max

doi:10.1093/carcin/bgn084

Cited by 83 publications

(59 citation statements)

References 30 publications

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“…C2C12 thus appeared to be particularly prone to histone modifications triggered by short term tungsten-alloy exposure with minimal impact on cell viability. We did not detect any effect of nickel on H3-Ser10 phosphorylation as opposed to the previous study that reported nickel mediated increased H3-Ser10 phosphorylation in human lung carcinoma A549 cultures (Ke et al, 2008). Also, methylation levels at trimethyl-H3-Lys4 appeared to be unaffected in all our culture systems even at high concentrations of cobalt in contrast to increased methylation of H3-Lys4 reported in A549 cells (Li, xet al, 2009).…”

Section: Discussioncontrasting

confidence: 99%

In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components

Verma¹,

Xu²,

Jaiswal³

et al. 2011

Toxicology and Applied Pharmacology

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In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components" (2011 Tungsten-alloy has carcinogenic potential as demonstrated by cancer development in rats with intramuscular implanted tungsten-alloy pellets. This suggests a potential involvement of epigenetic events previously implicated as environmental triggers of cancer. Here, we tested metal induced cytotoxicity and epigenetic modifications including H3 acetylation, H3-Ser10 phosphorylation and H3-K4 trimethylation. We exposed human embryonic kidney (HEK293), human neuroepithelioma (SKNMC), and mouse myoblast (C2C12) cultures for 1-day and hippocampal primary neuronal cultures for 1-week to 50-200 μg/ml of tungsten-alloy (91% tungsten/6% nickel/3% cobalt), tungsten, nickel, and cobalt. We also examined the potential role of intracellular calcium in metal mediated histone modifications by addition of calcium channel blockers/chelators to the metal solutions. Tungsten and its alloy showed cytotoxicity at concentrations N 50 μg/ml, while we found significant toxicity with cobalt and nickel for most tested concentrations. Diverse cell-specific toxic effects were observed, with C2C12 being relatively resistant to tungsten-alloy mediated toxic impact. Tungsten-alloy, but not tungsten, caused almost complete dephosphorylation of H3-Ser10 in C2C12 and hippocampal primary neuronal cultures with H3-hypoacetylation in C2C12. Dramatic H3-Ser10 dephosphorylation was found in all cobalt treated cultures with a decrease in H3 pan-acetylation in C2C12, SKNMC and HEK293. Trimethylation of H3-K4 was not affected. Both tungsten-alloy and cobalt mediated H3-Ser10 dephosphorylation were reversed with BAPTA-AM, highlighting the role of intracellular calcium, confirmed with 2-photon calcium imaging. In summary, our results for the first time reveal epigenetic modifications triggered by tungsten-alloy exposure in C2C12 and hippocampal primary neuronal cultures suggesting the underlying synergistic effects of tungsten, nickel and cobalt mediated by changes in intracellular calcium homeostasis and buffering.Published by Elsevier Inc.

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Section: Discussioncontrasting

confidence: 99%

In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components

Verma¹,

Xu²,

Jaiswal³

et al. 2011

Toxicology and Applied Pharmacology

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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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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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“…The same cell cycle dependence of p-H3S10 was also demonstrated in plant and lower eukaryotic cells (7,8). In mammalian cells, H3S10 is primarily phosphorylated by Aurora B during mitosis (9), whereas its phosphorylation is regulated by c-Jun aminoterminal kinase/mitogen-activated protein (JNK/MAP) kinases when the cells are exposed heavy metals such as nickel (10).…”

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Phosphorylation of H3S10 Blocks the Access of H3K9 by Specific Antibodies and Histone Methyltransferase

Duan

Chen

Costa

et al. 2008

Journal of Biological Chemistry

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Post-translational modifications of histones play a critical role in regulating genome structures and integrity. We have focused on the regulatory relationship between covalent modifications of histone H3 lysine 9 (H3K9) and H3S10 during the cell cycle. Immunofluorescence microscopy revealed that H3S10 phosphorylation in HeLa, A549, and HCT116 cells was high during prophase, prometaphase, and metaphase, whereas H3K9 monomethylation (H3K9me1) and dimethylation (H3K9me2), but not H3K9 trimethylation (H3K9me3), were significantly suppressed. When H3S10 phosphorylation started to diminish during anaphase, H3K9me1 and H3K9me2 signals reemerged. Western blot analyses confirmed that mitotic histones, extracted in an SDS-containing buffer, had little H3K9me1 and H3K9me2 signals but abundant H3K9me3 signals. However, when mitotic histones were extracted in the same buffer without SDS, the difference in H3K9me1 and H3K9me2 signals between interphase and mitotic cells disappeared. Removal of H3S10 phosphorylation by pretreatment with -phosphatase unmasked mitotic H3K9me1 and H3K9me2 signals detected by both fluorescence microscopy and Western blotting. Further, H3S10 phosphorylation completely blocked methylation of H3K9 but not demethylation of the same residue in vitro. Given that several conserved motifs consisting of a Lys residue immediately followed by a Ser residue are present in histone tails, our studies reveal a potential new mechanism by which phosphorylation not only regulates selective access of methylated lysines by cellular factors but also serves to preserve methylation patterns and epigenetic programs during cell division.

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Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway

Cited by 83 publications

References 30 publications

In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components

In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components

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

Phosphorylation of H3S10 Blocks the Access of H3K9 by Specific Antibodies and Histone Methyltransferase

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