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. pmc Molecular responses to hypoxia-inducible factor 1α and beyond
    Jason Brocato
    Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York
    Mol Pharmacol 85:651-7. 2014
  2. pmc The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects
    Adriana Arita
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
    J Trace Elem Med Biol 26:174-8. 2012
  3. pmc Gene expression changes in human lung cells exposed to arsenic, chromium, nickel or vanadium indicate the first steps in cancer
    Hailey A Clancy
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Department of Environmental Health Sciences, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Metallomics 4:784-93. 2012
  4. pmc The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals
    Yana Chervona
    Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY 10987, USA
    Free Radic Biol Med 53:1041-7. 2012
  5. pmc Associations between arsenic exposure and global posttranslational histone modifications among adults in Bangladesh
    Yana Chervona
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA
    Cancer Epidemiol Biomarkers Prev 21:2252-60. 2012
  6. pmc Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects
    Adriana Arita
    New York University School of Medicine, NelsonInstitute of Environmental Medicine, New York, NY, USA
    Cancer Epidemiol Biomarkers Prev 22:261-9. 2013
  7. pmc Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis
    Jason Brocato
    Nelson Institute of Environmental Medicine, New York University School of Medicine, NY 10987, USA
    Crit Rev Toxicol 43:493-514. 2013
  8. pmc Sodium metavanadate exhibits carcinogenic tendencies in vitro in immortalized human bronchial epithelial cells
    Lisa Passantino
    New York University, Department of Environmental Medicine, 57 Old Forge Road, Tuxedo, New York, USA
    Metallomics 5:1357-67. 2013
  9. pmc Hypoxia and nickel inhibit histone demethylase JMJD1A and repress Spry2 expression in human bronchial epithelial BEAS-2B cells
    Haobin Chen
    Department of Environmental Medicine, New York University of School of Medicine, 550 First Avenue, New York, NY 10016, USA
    Carcinogenesis 31:2136-44. 2010
  10. pmc Comparison of gene expression profiles in chromate transformed BEAS-2B cells
    Hong Sun
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
    PLoS ONE 6:e17982. 2011

Scientific Experts

  • Max Costa
  • Haobin Chen
  • Adriana Arita
  • Hong Sun
  • Qin Li
  • Thomas Kluz
  • Xue Zhou
  • Yana Chervona
  • Thomas P Ellen
  • Jason Brocato
  • Qingdong Ke
  • Fen Wu
  • Kathrin Kiok
  • Lisa Passantino
  • Hailey A Clancy
  • Alexandra Muñoz
  • Jiri Zavadil
  • Kam Meng Tchou-Wong
  • Dongyun Zhang
  • Ahmed N Uddin
  • Alexandra B Muñoz
  • Mary V Gamble
  • Maria Antonietta Zoroddu
  • Eunus Ali
  • Xinhua Liu
  • Hsiang Chi Tseng
  • Megan N Hall
  • Mohammad Nasir Uddin
  • Hailey Clancy
  • Stuart Brown
  • Sutapa Bose
  • Phillip R Smith
  • Zuojian Tang
  • Harriet A Clancy
  • Chuanshu Huang
  • Jingxia Li
  • Jimin Gao
  • Mark E Harder
  • Jingxiang Bai
  • Judy Xiong
  • Catherine B Klein
  • Wei Dai
  • Xin Liu
  • Ting Chung Suen
  • Adrienne D Kurtz
  • Thomas J Begley
  • John P Rooney
  • Fredric J Burns
  • Toby G Rossman

Detail Information

Publications32

  1. pmc Molecular responses to hypoxia-inducible factor 1α and beyond
    Jason Brocato
    Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York
    Mol Pharmacol 85:651-7. 2014
    ..In this review, we will focus on recent insights into HIF-1α regulation, function, and gene expression. We will also discuss emerging data on the involvement of HIF in cancer prognosis and therapeutic interventions. ..
  2. pmc The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects
    Adriana Arita
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
    J Trace Elem Med Biol 26:174-8. 2012
    ....
  3. pmc Gene expression changes in human lung cells exposed to arsenic, chromium, nickel or vanadium indicate the first steps in cancer
    Hailey A Clancy
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Department of Environmental Health Sciences, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Metallomics 4:784-93. 2012
    ....
  4. pmc The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals
    Yana Chervona
    Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, NY 10987, USA
    Free Radic Biol Med 53:1041-7. 2012
    ..The sources of oxidative stress discussed here are carcinogenic metals, such as, nickel, arsenic, and chromium...
  5. pmc Associations between arsenic exposure and global posttranslational histone modifications among adults in Bangladesh
    Yana Chervona
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA
    Cancer Epidemiol Biomarkers Prev 21:2252-60. 2012
    ..Arsenic compounds are weakly mutagenic, alter gene expression and posttranslational histone modifications (PTHMs) in vitro...
  6. pmc Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects
    Adriana Arita
    New York University School of Medicine, NelsonInstitute of Environmental Medicine, New York, NY, USA
    Cancer Epidemiol Biomarkers Prev 22:261-9. 2013
    ....
  7. pmc Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis
    Jason Brocato
    Nelson Institute of Environmental Medicine, New York University School of Medicine, NY 10987, USA
    Crit Rev Toxicol 43:493-514. 2013
    ..Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance...
  8. pmc Sodium metavanadate exhibits carcinogenic tendencies in vitro in immortalized human bronchial epithelial cells
    Lisa Passantino
    New York University, Department of Environmental Medicine, 57 Old Forge Road, Tuxedo, New York, USA
    Metallomics 5:1357-67. 2013
    ....
  9. pmc Hypoxia and nickel inhibit histone demethylase JMJD1A and repress Spry2 expression in human bronchial epithelial BEAS-2B cells
    Haobin Chen
    Department of Environmental Medicine, New York University of School of Medicine, 550 First Avenue, New York, NY 10016, USA
    Carcinogenesis 31:2136-44. 2010
    ..Taken together, our results suggest that histone demethylases could be targets of environmental carcinogens and their inhibition may lead to altered gene expression and eventually carcinogenesis...
  10. pmc Comparison of gene expression profiles in chromate transformed BEAS-2B cells
    Hong Sun
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
    PLoS ONE 6:e17982. 2011
    ....
  11. pmc Effects of nickel treatment on H3K4 trimethylation and gene expression
    Kam Meng Tchou-Wong
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
    PLoS ONE 6:e17728. 2011
    ..This study may provide insights into the epigenetic mechanism(s) underlying the carcinogenicity of nickel compounds...
  12. pmc Liprin-α4 is required for nickel induced receptor protein tyrosine phosphatase-leukocyte antigen related receptor F (RPTP-LAR) activity
    Kathrin Kiok
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America
    PLoS ONE 6:e22764. 2011
    ..Liprin-α4 appeared necessary for the nickel induced tyrosine phosphatase activity. The presence of Liprin-α4 and nickel increased tyrosine phosphatase activity that reduced the global levels of tyrosine phosphorylation in the cell...
  13. pmc Global levels of histone modifications in peripheral blood mononuclear cells of subjects with exposure to nickel
    Adriana Arita
    Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
    Environ Health Perspect 120:198-203. 2012
    ..Ni compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the Ni-induced changes in global histone modification levels have only been tested in vitro...
  14. pmc Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro
    Fen Wu
    Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA
    Toxicol Appl Pharmacol 258:166-75. 2012
    ..EGCG, therefore, might serve as a potential chemopreventive agent against Cr(VI) carcinogenesis...
  15. pmc Elucidating the mechanisms of nickel compound uptake: a review of particulate and nano-nickel endocytosis and toxicity
    Alexandra Muñoz
    New York University School of Medicine, Nelson Institute of Environmental Medicine, 57 Old Forge Road, NY 10987, USA
    Toxicol Appl Pharmacol 260:1-16. 2012
    ..In this regard, this review aims to carefully document one system (particulate nickel compound uptake) and characterize its properties...
  16. pmc Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase
    Xue Zhou
    Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA
    Cancer Res 70:4214-21. 2010
    ..Thus, these results indicate that hypoxia might target JARID1A activity, which in turn increases H3K4me3 at both the global and gene-specific levels, leading to the altered programs of gene expression and tumor progression...
  17. pmc Nickel ions inhibit histone demethylase JMJD1A and DNA repair enzyme ABH2 by replacing the ferrous iron in the catalytic centers
    Haobin Chen
    Department of Environmental Medicine, New York University of School of Medicine, New York, New York 10016, USA
    J Biol Chem 285:7374-83. 2010
    ..Inhibition of these dioxygenases by nickel is likely to have widespread impacts on cells (e.g. impaired epigenetic programs and DNA repair) and may eventually lead to cancer development...
  18. pmc 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...
  19. pmc 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...
  20. pmc 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...
  21. pmc 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...
  22. pmc 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...
  23. pmc 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...
  24. pmc 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...
  25. pmc 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
    ....
  26. pmc 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
    ....
  27. pmc 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
    ....
  28. pmc 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...
  29. pmc 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...
  30. pmc 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))...
  31. pmc 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...
  32. 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
    ....