Abstract
Nickel compounds are important occupational and environmental pollutants. Chronic exposure to these pollutants has been connected with increased risks of respiratory cancers and cardiovascular diseases. However, it is still not clear what are the specific molecular targets for nickel toxicity and carcinogenicity. Here, we propose that the iron- and 2-oxoglutarate-dependent dioxygenase family enzymes are important intracellular targets that mediate the toxicity and carcinogenicity of nickel. In support of this hypothesis, our data show that three different classes of enzymes in this iron- and 2-oxoglutarate-dependent dioxygenase family, including HIF-prolyl hydroxylase PHD2, histone demethylase JHDM2A/JMJD1A, and DNA repair enzyme ABH3, are all highly sensitive to nickel inhibition. Inactivation of these enzymes accounts for a number of deleterious effects caused by nickel in cells, namely hypoxia-mimic stress and aberrant epigenetic changes. Future studies on nickel’s effects on these iron- and 2-oxoglutarate-dependent dioxygenases would deepen our understanding on nickel toxicity and carcinogenicity.
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Acknowledgments
We thank Dr. Yi Zhang for providing the Flag-tagged JHDM2A insect cell expression vector and Dr. Timothy R. O’Connor for the 6×His-tagged ABH3 bacterial expression vector. This work was supported by grant numbers ES005512 and ES014454 from the National Institute of Environmental Health Sciences.
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Chen, H., Costa, M. Iron- and 2-oxoglutarate-dependent Dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity. Biometals 22, 191–196 (2009). https://doi.org/10.1007/s10534-008-9190-3
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DOI: https://doi.org/10.1007/s10534-008-9190-3