Water Insoluble nickel compounds vary in their carcinogenic potency due to a selectivity in the ability of the particles to be phagocytized by target cells. In the acidified phagosomes, ionic nickel is released, ultimately making its way into the nucleus. Ni ions cause an increase in DNA methylation we believe by inhibiting Fe dependent histone demethylases such as those responsible for demethylating H3K9 mono and dimethyl. This results in gene silencing. Nickel ions also inhibit the Jarid-1 family of histone demethylases which result in an increase in H3K4 trimethylation causing genes to be turned on. The dioxygenase superfamily of enzymes are the major targets for Nickel ions in cells and one member of this family are the Prolyl Hydroxylases that cause Hypoxia Inducible Factor (HIF-1 alpha) to be degraded. Inhibition of these dioxygenases by Nickel ions stabilizes HIF-1 alpha and turns on or off all HIF-1 alpha dependent genes. We have used Chip-on-chip as well as Chip-seq to map the H3K4 trimethylation changes in the genome and correlated this with RNA expression using RNA-seq. We have determined the binding constant of JHDM2A for Ni ions to be 1.7uM which is three times better than that for Fe which is bound to the active site of the enzyme. Using X-ray photo-electron spectroscopy we have determined that Ni ions bind in place of Fe to exactly the same ligands as Fe in the active site of the enzyme. Knockdown of JHDM2A as well as Nickel ion treatment results in the transformation of BEAS-2B cells to anchorage independent growth. Sprly2 and Cldn1 are down regulated by Ni inhibition of JHDM2A and these genes remain silenced after Nickel is removed and in the Nickel transformed cells. Forced expression of Sprly2 prevents Ni ion induced cell transformation and tranfection of Cldn1 reverses cell transformation induced by Nickel ions. Our goal of these studies is to prove that the inhibition of a histone demethylase JHDM2A by Ni ions is responsible for cell transformation.
Professor, Department of Environmental Medicine
Professor, Department of Biochemistry and Molecular Pharmacology
Chair, Department of Enviromental Medicine
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