Nickel (Ni) compounds are known carcinogens and the carcinogenicity of different forms of Ni compounds varies with their water solubility. Due to their weak mutagenecity, epigenetic mechanisms likely play an important role in Ni carcinogenesis. This project investigated epigenetic effects of Ni compounds in cells. The results demonstrated that both water soluble and insoluble Ni compounds were taken up by cells, resulting in Ni ion accumulation in the cytoplasm and nucleus. When the exposure was ceased, Ni ions persisted in both sites in the insoluble Ni-exposed cells longer than in the soluble Ni-exposed ones. It was found that Ni exposure caused alterations in histone modifications at the global level in cells. Among these were: loss of acetylation of all four core histones, and increases of H3K9 dimethylation. These changes in histone modification were implicated in Ni-induced transgene silencing. In addition, Ni exposure also resulted in an increase in H3S10 phosphorylation and ubiquitination of H2A and H2B. Exploration of the mechanisms by which Ni induced these increases in histone modifications revealed that Ni activated JNK-MAPK pathway which induced H3S10 phosphorylation. In vitro studies of histone ubiquitination and deubiquitination suggested that Ni elevated histone ubiquitination by inhibition the deubiquitinating enzyme activity. These studies have demonstrated strong epigenetic effects of Ni in cells which are important in its toxicity and carcinogenicity. In addition, the results present a likely explanation for the difference in carcinogenicity between water soluble and insoluble Ni compounds in experimental animals, as well as suggesting a possible mechanism for why insoluble Ni compounds are more potent carcinogens than the soluble species.
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