Hypoxia Signaling, Chromatin Remodeling and Nickel Carcinogenesis

Summary

Principal Investigator: Max Costa
Affiliation: New York University School of Medicine
Country: USA
Abstract: The long-range goals of this grant proposal are to study the involvement of the hypoxia signaling pathway upon chromatin remodeling, gene silencing, and cell transformation. Hypoxia or agents that mimic hypoxia cause a global loss of histone acetylation and increase the methylation of H3 lysine 9 which is the chromatin mark of gene silencing for the individual nucleosomes. Methylation of H3 lysine 9 leads to DNA methylation and inherited gene silencing. We will study the ability of hypoxia and agents that activate hypoxia signaling (NiCI2, CoCI2, deferoxamine, and DMOG) to induce cell transformation in wild-type or in HIF-1alpha knockout mouse embryo fibroblast (MEF). We will transfect a normal HIF-1alpha construct into MEF cells with a knockout of this gene to study whether we can restore their ability to be transformed by hypoxia and agents that mimic hypoxia. We will also stably transfect mutated HIF-1alpha constructs that will constitutively express HIF in its stabile and or stable/active form into MEF HIF+/- cells and study the effect of stabilized and/or activated HIF- 1alpha on anchorage-independent growth and tumor formation in nude mice. We will investigate global changes in H3K9 acetylation, H3K9 methylation, G9a activity (enzyme that dimethylates H3K9) and DNA methylation in MEF with intact or knockout of HIF-1alpha following exposure to hypoxia or agents that mimic hypoxia. We will also utilize the expression levels of DHFR and DNA mismatch repair gene Mlh1 which are down-regulated by hypoxia signaling to study gene specific effects of chromatin remodeling induced by hypoxia signaling using CHIP assays targeted to their promoters with antibodies specific to H3K9 dimethylation and/or H3K9 acetylation. We have obtained mouse embryonic stem cell wild-type (WT), G9a knockout (G9a-/-) and G9a-/- stably transfected with wild-type G9a (G9a-/- + G9a WT), and we will utilize these cells to address the role of G9a in mediating histone methylation H3K9 and the effects of hypoxia signaling on DNA methylation and DHFR/MIh expression. We will study the reversibility and stability of MEF cells that have already been transformed via the hypoxia pathway to chromatin remodeling agents and R59949 (HIF inhibitor). These studies will allow us to understand the importance of hypoxia signaling and the HIF-1alpha transcription factor in promoting neoplastic cell transformation.
Funding Period: 2006-08-16 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice
    Ahmed N Uddin
    Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Toxicol Appl Pharmacol 221:329-38. 2007
  2. ncbi Mechanisms of c-myc degradation by nickel compounds and hypoxia
    Qin Li
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA
    PLoS ONE 4:e8531. 2009
  3. ncbi A genome-wide deletion mutant screen identifies pathways affected by nickel sulfate in Saccharomyces cerevisiae
    Adriana Arita
    New York University School of Medicine, Nelson Institute of Environmental Medicine, NY 10987, USA
    BMC Genomics 10:524. 2009
  4. ncbi A genome-wide screen in Saccharomyces cerevisiae reveals pathways affected by arsenic toxicity
    Xue Zhou
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
    Genomics 94:294-307. 2009
  5. ncbi c-Myc mediates a hypoxia-induced decrease in acetylated histone H4
    Qin Li
    New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY 10987, USA
    Biochimie 91:1307-10. 2009
  6. ncbi Alterations of histone modifications by cobalt compounds
    Qin Li
    Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Carcinogenesis 30:1243-51. 2009
  7. ncbi Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium
    Hong Sun
    Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA
    Toxicol Appl Pharmacol 237:258-66. 2009
  8. ncbi Effects of nickel, chromate, and arsenite on histone 3 lysine methylation
    Xue Zhou
    Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, NY 10987, USA
    Toxicol Appl Pharmacol 236:78-84. 2009
  9. ncbi Heterochromatinization as a potential mechanism of nickel-induced carcinogenesis
    Thomas P Ellen
    Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
    Biochemistry 48:4626-32. 2009
  10. ncbi Nickel compounds induce apoptosis in human bronchial epithelial Beas-2B cells by activation of c-Myc through ERK pathway
    Qin Li
    New York University School of Medicine, Nelson Institute of Environmental Medicine, 57 Old Forge Road, NY 10987, USA
    Toxicol Appl Pharmacol 235:191-8. 2009

Scientific Experts

  • Adriana Arita
  • Max Costa
  • Qin Li
  • Hong Sun
  • Xue Zhou
  • Thomas P Ellen
  • Haobin Chen
  • Qingdong Ke
  • Thomas Kluz
  • Dongyun Zhang
  • Ahmed N Uddin
  • Jingxia Li
  • Jimin Gao
  • Chuanshu Huang
  • Mark E Harder
  • Adrienne D Kurtz
  • Thomas J Begley
  • Judy Xiong
  • Jingxiang Bai
  • Catherine B Klein
  • Wei Dai
  • Xin Liu
  • John P Rooney
  • Ting Chung Suen
  • Fredric J Burns
  • Toby G Rossman

Detail Information

Publications15

  1. ncbi Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice
    Ahmed N Uddin
    Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Toxicol Appl Pharmacol 221:329-38. 2007
    ....
  2. ncbi Mechanisms of c-myc degradation by nickel compounds and hypoxia
    Qin Li
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA
    PLoS ONE 4:e8531. 2009
    ..Our study demonstrated that Nickel and hypoxia exposure increased c-myc T58 phosphorylation and decreased USP28 protein levels in cancer cells, which both lead to enhanced c-myc ubiquitination and proteasomal degradation...
  3. ncbi A genome-wide deletion mutant screen identifies pathways affected by nickel sulfate in Saccharomyces cerevisiae
    Adriana Arita
    New York University School of Medicine, Nelson Institute of Environmental Medicine, NY 10987, USA
    BMC Genomics 10:524. 2009
    ..cerevisiae gene deletion strains (the entire set of nonessential genes for this organism) to identify gene products that modulate cellular toxicity to nickel sulfate (NiSO(4))...
  4. ncbi A genome-wide screen in Saccharomyces cerevisiae reveals pathways affected by arsenic toxicity
    Xue Zhou
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
    Genomics 94:294-307. 2009
    ..Our studies have potential implications for understanding toxicity and carcinogenesis in arsenic-induced human conditions, such as cancer and aging...
  5. ncbi c-Myc mediates a hypoxia-induced decrease in acetylated histone H4
    Qin Li
    New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY 10987, USA
    Biochimie 91:1307-10. 2009
    ..The decrease in c-Myc protein levels induced by hypoxia may contribute to hypoxia-induced gene repression...
  6. ncbi Alterations of histone modifications by cobalt compounds
    Qin Li
    Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Carcinogenesis 30:1243-51. 2009
    ....
  7. ncbi Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium
    Hong Sun
    Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA
    Toxicol Appl Pharmacol 237:258-66. 2009
    ....
  8. ncbi Effects of nickel, chromate, and arsenite on histone 3 lysine methylation
    Xue Zhou
    Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, NY 10987, USA
    Toxicol Appl Pharmacol 236:78-84. 2009
    ....
  9. ncbi Heterochromatinization as a potential mechanism of nickel-induced carcinogenesis
    Thomas P Ellen
    Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA
    Biochemistry 48:4626-32. 2009
    ..We conclude that condensation of chromatin by nickel is a potential mechanism of nickel-mediated gene regulation...
  10. ncbi Nickel compounds induce apoptosis in human bronchial epithelial Beas-2B cells by activation of c-Myc through ERK pathway
    Qin Li
    New York University School of Medicine, Nelson Institute of Environmental Medicine, 57 Old Forge Road, NY 10987, USA
    Toxicol Appl Pharmacol 235:191-8. 2009
    ..Collectively, the results demonstrate that c-Myc induction by nickel ions occurs via an ERK-dependent pathway and plays a crucial role in nickel-induced apoptosis in Beas-2B cells...
  11. ncbi Iron- and 2-oxoglutarate-dependent dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity
    Haobin Chen
    Department of Environmental Medicine, New York University School of Medicine, New York, NY 10987, USA
    Biometals 22:191-6. 2009
    ..Future studies on nickel's effects on these iron- and 2-oxoglutarate-dependent dioxygenases would deepen our understanding on nickel toxicity and carcinogenicity...
  12. ncbi Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway
    Qingdong Ke
    Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
    Carcinogenesis 29:1276-81. 2008
    ..It is likely that modification of H3S10 is one of a growing number of epigenetic changes believed to be involved in the carcinogenesis caused by Ni...
  13. ncbi Arsenite alters global histone H3 methylation
    Xue Zhou
    Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Carcinogenesis 29:1831-6. 2008
    ..Future studies in our laboratory will address the genomic location of these silencing and activating marks using ChIP-on-chip technology...
  14. ncbi Nickel compounds induce histone ubiquitination by inhibiting histone deubiquitinating enzyme activity
    Qingdong Ke
    Department of Environmental Medicine, New York University School of Medicine, 650 First Avenue, New York, NY 10016, USA
    Toxicol Appl Pharmacol 228:190-9. 2008
    ..The study provides further evidence that supports the notion that nickel ions alter epigenetic homeostasis in cells, which may lead to altered programs of gene expression and carcinogenesis...
  15. ncbi JNK1 mediates degradation HIF-1alpha by a VHL-independent mechanism that involves the chaperones Hsp90/Hsp70
    Dongyun Zhang
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA
    Cancer Res 70:813-23. 2010
    ..Taken together, our studies define a novel function for JNK1 in regulating HIF-1alpha turnover by a VHL-independent mechanism...