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Max Costa

Max Costa

Chair, Department of Enviromental Medicine

Professor, Department of Environmental Medicine

Professor, Department of Biochemistry and Molecular Pharmacology

Keywords
molecular mechanisms of metal carcinogenesis, cancer, pharmacology, Epigenetics , chromatin structure
Summary

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.


 




 

Phone

646-754-9443

Academic office

341 east 25th street

first floor

New York , NY 10010

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Professor, Department of Environmental Medicine

Professor, Department of Biochemistry and Molecular Pharmacology

Chair, Department of Enviromental Medicine

University of Arizona Medical School , Radiation Oncology

Chen, Qiao Yi; Murphy, Anthony; Sun, Hong; Costa, Max

Toxicology & applied pharmacology. 2019 Jun 19; 114636

Chen, Qiao Yi; Des Marais, Thomas; Costa, Max

Carcinogenesis. 2019 May 14; 40(3):393-402

DesMarias, T L; Costa, M

Current opinion in toxicology. 2019 April; 14(pp):1-7

Chen, Qiao Yi; DesMarais, Thomas; Costa, Max

Annual review of pharmacology & toxicology. 2019 Jan 06; 59:537-554

Chen, Qiao Yi; Li, Jinquan; Sun, Hong; Wu, Feng; Zhu, Yusha; Kluz, Thomas; Jordan, Ashley; DesMarais, Thomas; Zhang, Xiaoru; Murphy, Anthony; Costa, Max

Molecular carcinogenesis. 2018 Aug; 57(8):968-977

Chen, Qiao Yi; Costa, Max

Molecular pharmacology. 2018 Jul; 94(1):784-792

Munoz, Alexandra; Eldridge, Will J; Jakobsen, Nina Munkholt; Sorensen, Helle; Wax, Adam; Costa, Max

Carcinogenesis. 2018 02 09; 39(2):109-117