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Max Costa

Max Costa

Chair, Department of Environmental Medicine

Professor, Department of Medicine

Professor, Department of Biochemistry and Molecular Pharmacology

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

Water insoluble nickel (Ni) 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 Ni is released, ultimately making its way into the nucleus. Ni ions cause an increase in DNA methylation we believe by inhibiting iron (Fe)-dependent histone demethylases such as those responsible for demethylating H3K9 mono and dimethyl. This results in gene silencing. Ni 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 Ni 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 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 Ni is removed and in the Ni transformed cells. Forced expression of Sprly2 prevents Ni ion induced cell transformation and transfection of Cldn1 reverses cell transformation induced by Ni 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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University of Arizona Medical School , Radiation Oncology

Liu, Shan; Costa, Max

Toxicology & applied pharmacology. 2022 Sep 15; 454:116244

Xu, Jiheng; Yang, Rui; Li, Jingxia; Wang, Lidong; Cohen, Mitchell; Simeone, Diane M; Costa, Max; Wu, Xue-Ru

Cancers. 2022 Aug 27; 14(17):

Zhang, Zhuo; Li, Jingxia; Yan, Bo; Tu, Huailu; Huang, Chao; Costa, Max

Heliyon. 2022 Aug; 8(8):e10086

Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Gorr, Matthew W; Wold, Loren E; Cohen, Mitchell D

International journal of environmental research & public health. 2022 Jan 14; 19(2):

Handbook on the Toxicology of Metals

Nordberg, Gunnar F.; Costa, Max

Handbook on the Toxicology of Metals. [S.l.] : Elsevier Inc., 2021. 5th ed.. 1 v. (5189432)

Sun, Hong; Costa, Max

Handbook on the Toxicology of Metals. [S.l.] : Elsevier Inc., 2021. 5th ed.. p.197-220. (5189452)

Fowler, Bruce A.; Chou, C. H.Selene J.; Jones, Robert L.; Costa, Max; Chen, Chien Jen

Handbook on the Toxicology of Metals. [S.l.] : Elsevier Inc., 2021. 5th ed.. p.41-89. (5189472)

Klein, Catherine B.; Costa, Max

Handbook on the Toxicology of Metals. [S.l.] : Elsevier Inc., 2021. 5th ed.. p.615-637. (5189482)