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

Abstract

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...

The Expression of Histone Demethylase JMJD1A in Renal Cell Carcinoma

“…Cobalt compounds or nickel compounds can alter the histone modification [27].They can affect the activity of histone demethylase such as inhibiting function of nickel ions on JMJD1A by replacing the ferrous iron in the catalytic centers [28]. Chronic exposure to nickel compounds has been connected to the increased risks of cancer, and alteration of histone modification may be one important factor [29].…”

Nicotinamide N-Methyltransferase Suppression Participates in Nickel-Induced Histone H3 Lysine9 Dimethylation in BEAS-2B Cells

“…Previous studies have shown that nickel increased H3K9 dimethylation by inhibiting the activity of Fe(II)-2-oxoglutarate-dependent histone H3K9 demethylase accompanied by inhibition of G9a methyltransferase [11, 32]. Further studies showed that histone-modifying enzymes, including acetyltransferases and methyltransferases, consumed the cellular intermediate metabolites acetyl-CoA and SAM as acetyl and methyl donors to promote histone acetylation and methylation, respectively [33].…”

Toxicogenomic effect of nickel and beyond

“…Ni (II) has been found to inhibit demethylase activity of KDM3A (JMJD1A) in vitro , and in turn led to an accumulation of dimethylation at histone H3 lysine 9 (H3K9me2) (Chen et al 2010a). The same study also showed that the activity of DNA repair enzyme ABH2 was inhibited by Ni (II).…”

“…The same study also showed that the activity of DNA repair enzyme ABH2 was inhibited by Ni (II). Extended X-ray absorption fine structure showed that the best fit for iron binding ABH2 consists of five oxygen/nitrogen donor ligands of which two are histidine ligands; and when nickel binds to ABH2, the binding site is indistinguishable from the iron-binding site (Chen et al 2010a). Isothermal titration calorimetry analysis suggested that Ni (II) binds to ABH2 with higher affinity than Fe (II).…”

“…Isothermal titration calorimetry analysis suggested that Ni (II) binds to ABH2 with higher affinity than Fe (II). It is likely that dioxygenases such as PHD family, JmjC-domain containing histone demethylases and ABH DNA repair enzymes use the same iron coordinating motif (His-Asp-His) to bind ferrous iron at their active sites, and Ni(II) competes with Fe(II) and replaces it at the iron-binding site (Chen et al 2010a; Gorres et al 2009). …”