Max Costa

Max Costa, PhD
Professor; Program Director of Perlmutter Cancer Center;
ChairmanDepartments of Environmental Medicine (Chair), Biochemistry and Molecular Pharmacology
New York University 57 Old Forge Road Tuxedo, New York 10987
United States of America
e-mail: max.costa@nyumc.org

Dr. Costa has been working in the area of epigenetics and cancer for over 20 years. He has studied how carcinogenic metals affect the epigenetic program through inhibition of histone demethylases. In particular, Dr. Costa has studied how Arsenic, Nickel and Chromate alter histone posttranslational modifications in chromatin using cell culture and in human PBMCs. Dr. Costa has also conducted ChIP-Seq using several histone marks and RNA-Seq following carcinogenic metal treatment of cells. He has been working on the mechanism of metal carcinogenesis for over 35 years.

Contribution to Science: Dr. Costa has studied the basis for the carcinogenic activity of various nickel compounds. Model compounds that were utilized included crystalline nickel sulfide and nickel subsulfide which are potent carcinogens at any site of administration to experimental animals whereas amorphous nickel sulfide lacked any activity (size <5u). Nickel subsulfide was present in the crushing operations of nickel refining where there was a high incidence of nasal and lung cancers. Using various tissue culture systems including target cells for transformation it was found that the carcinogenic nickel compounds were taken up into cells by phagocytosis while the noncarcinogenic compounds were not. The uptake of these particulate nickel compounds depended upon the surface charge of the particles. The crystalline nickel sulfide compounds had a negative surface charge and the amorphous nickel sulfide had a positive charge. Changing the amourphous nickel sulfide charge to a positive one, resulted in active uptake by phagocytosis and induction of cell transformation with a potency equivalent to the crystalline nickel compounds. The genotoxicity of nickel compounds was investigated and it was found that nickel exposure induced DNA repair, chromosomal aberrations, and sister chromatin exchange, but in general it exhibited low mutagenic activity. Then in 1991 my lab discovered that nickel could induce DNA hypermethylation targeted at turning off the expression of a senescence gene. The molecular mechanisms of nickel induced gene silencing was investigated further using transgenic cell lines where the endogenous HPGRT gene had been silenced with a mutation and single copies of a transgene (bacterial gpt gene) were inserted at different positions in the genome. When the transgene was placed near heterochromatin, nickel was able to silence it with DNA methylation; but when it was distant from heterochromatin, nickel was not able to silence the transgene. In later studies the mechanism of this silencing was delineated. Nickel ions could bind to the phosphate backbone of DNA better than and in place of magnesium and since most of the magnesium was present in heterochromatin, nickel caused enhanced condensation of heterochromatin and silenced genes that were near it. In another interesting set of studies nickel was found to bind to H4 anchoring on a histidine residue and produced a coordination of H4 that had a similar structure as H4 with all the lysines in the tail fully acetylated. In other studies nickel was also found to inhibit histone acetylation, and this may be the operative mechanism. Additional studies uncovered the major targets for nickel toxicity in the cell to be the alpha ketoglutarate dependent dioxygnease enzymes. The first of these enzymes studied were the prolyl hydroxylases that target the degredation of HIF-1 alpha but later these studies were extended to other dioxygenases such as ABH2, Tet protein and histone demethylases. Using ABH2 as a model, nickel was found to displace iron (Fe) from the active site of this enzyme. The affinity for nickel was 3 fold higher than that for Fe and the binding of Ni was favored. When Ni bound to these enzymes XAS studies showed it was hexacoordinated while Fe was pentacoordinated allowing one site for oxygen to bind, the binding of Ni completely and permanently inactivated these enzymes resulting in increase in HIF-1 alpha protein, increases in histone lysine methylation and increased DNA methylation as a result of inhibition of the Tet protein. In fact Ni exposure in nickel refinery workers demonstrated increased Histone methylation and striking changes in gene expression in PBMC. Dr. Costa has also studied other metals in terms of epigenetic effects including arsenic, chromate and cadmium. Arsenic, for example, epigenetically silenced the expression of the stem loop binding protein which was required to translate canonical histones that do not have a Poly A tail. This resulted in these histones acquiring a Poly A tail by default and histones such as H3.1 had Poly A tails and were present at other phases of the cell cycle besides S phase. Recent studies demonstrated that transfection of H3.1 such that it acquires a Poly A tail was able to transform Beas2B cells to anchorage independent growth.