HYPOXIA AND GENE REPRESSION

Summary

Principal Investigator: Amato J Giaccia
Abstract: DESCRIPTION (provided by applicant): The tumor microenvironment influences both therapeutic outcome and malignant progression. In particular, tumor hypoxia has been shown to be a prognostic indicator for poor therapeutic response, to increase genomic instability, and to induce the expression of genes that increase metastatic spread. Previous studies from my laboratory have indicated that hypoxia induces apoptosis in oncogenically transformed cells in vitro, acts as a selective pressure for the expansion of transformed cells possessing diminished apoptotic potential, and co- localizes with apoptotic regions in tumors. The tumor suppressor protein p53 induces rapid apoptosis in response to oxygen concentrations that induce an S-phase arrest. Hypoxia-induced p53 is nuclear and associates with p53-response elements in target genes, such as mdm2 and p21. Our previous studies have shown that the cellular decision to use p53 transactivation or transrepression is mediated after stress-induced binding of p53 to the promoter, and is determined by the presence of co-activators or co-repressors. In contrast to p53 induced by DNA-damaging agents, hypoxia-induced p53 acts primarily as a repressor. Using extensive microarray analysis, we identified families of repressed targets of p53 that are involved in cell signaling, DNA repair, cell-cycle control and differentiation. A chromatin immunoprecipitation screen demonstrated that p53 induced by either hypoxia or DNA damage binds to the same promoters, regardless of transcriptional outcome. We have also observed that several genes repressed by p53 in normoxia and hypoxia do not appear to have detectable binding by p53 as assayed by chromatin immunoprecipitation. In pursuing this interesting observation, we discovered that at least one of these genes (WNT16B) is regulated through differential histone methylation. This has led to the discovery that the transcriptional repressor JARID1B is a direct p53 target. In a parallel set of studies, we have also determined that HIF is a direct regulator of three Jumonji-domain histone demethylases, including JARID1B. JARID1B represses expression of the proliferative gene CDK6 under hypoxia. The critical hypothesis that we will be testing is whether induction of JARID1B by p53 and/or HIF represses the expression of genes critical for a tumorigenic phenotype. We will test these hypotheses through a combination of genetic and biochemical approaches in cell lines and in mice. By identifying and characterizing the genes repressed by p53 and HIF through JARID1B during hypoxia, our studies should clarify some of the complex regulatory mechanisms activated in the hypoxic microenvironment.
Funding Period: 2000-07-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. ncbi The roles of Chk 1 and Chk 2 in hypoxia and reoxygenation
    Ester M Hammond
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, California 94303 5152, USA
    Cancer Lett 238:161-7. 2006
  2. pmc PHD2 in tumour angiogenesis
    D A Chan
    Department of Radiation Oncology, University of California, 2340 Sutter Street, S 332, Box 1331, San Francisco, CA 94143 1331, USA
    Br J Cancer 103:1-5. 2010
  3. pmc Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species
    David A Patten
    Centre de recherche du CHUQ, L Hôtel Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec, QC, G1R 2J6, Canada
    Mol Biol Cell 21:3247-57. 2010
  4. pmc Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress
    Scott M Welford
    Department of Radiation Oncology, Stanford University School of Medicine, 1235 CCSR, 269 Campus Drive, Stanford, CA 93025, USA
    Mol Cell Biol 30:4595-603. 2010
  5. pmc Hypoxia and senescence: the impact of oxygenation on tumor suppression
    Scott M Welford
    Department of Radiation Oncology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, BRB 325, Cleveland, OH 44106, USA
    Mol Cancer Res 9:538-44. 2011
  6. pmc Harnessing synthetic lethal interactions in anticancer drug discovery
    Denise A Chan
    Department of Radiation Oncology, University of California, San Francisco, California 94143 1331, USA
    Nat Rev Drug Discov 10:351-64. 2011
  7. pmc The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO
    Erinn B Rankin
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303 5152, USA
    Cell 149:63-74. 2012
  8. pmc Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes
    Cullen M Taniguchi
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford, California, USA
    Nat Med 19:1325-30. 2013
  9. pmc The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia-inducible factor 1 target gene and promotes survival and proliferation of VHL-deficient renal cancer cells
    Olga V Razorenova
    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, California, USA
    Mol Cell Biol 34:739-51. 2014
  10. pmc MiR-210--micromanager of the hypoxia pathway
    Xin Huang
    Magee Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Trends Mol Med 16:230-7. 2010

Research Grants

  1. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013
  2. Mdig gene and histone demethylation in lung cancer
    Fei Chen; Fiscal Year: 2013
  3. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  4. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
  5. MECHANISMS OF BREAST DEVELOPMENT AND CARCINOGENESIS
    Robert A Weinberg; Fiscal Year: 2013
  6. Role of the Y-Located TSPY Gene in Human Oncogenesis
    Yun Fai Chris Lau; Fiscal Year: 2013

Detail Information

Publications20

  1. ncbi The roles of Chk 1 and Chk 2 in hypoxia and reoxygenation
    Ester M Hammond
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, California 94303 5152, USA
    Cancer Lett 238:161-7. 2006
    ..Loss or inhibition of either kinase sensitizes cells to hypoxia/reoxygenation indicating that either or both could represent significant therapeutic targets...
  2. pmc PHD2 in tumour angiogenesis
    D A Chan
    Department of Radiation Oncology, University of California, 2340 Sutter Street, S 332, Box 1331, San Francisco, CA 94143 1331, USA
    Br J Cancer 103:1-5. 2010
    ..This review summarises our current understanding of PHD2 and tumour angiogenesis, focusing on the influences of PHD2 on vascular normalisation and neovascularisation...
  3. pmc Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species
    David A Patten
    Centre de recherche du CHUQ, L Hôtel Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec, QC, G1R 2J6, Canada
    Mol Biol Cell 21:3247-57. 2010
    ..However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions...
  4. pmc Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress
    Scott M Welford
    Department of Radiation Oncology, Stanford University School of Medicine, 1235 CCSR, 269 Campus Drive, Stanford, CA 93025, USA
    Mol Cell Biol 30:4595-603. 2010
    ..Together, these data demonstrate that in vivo oxygenation promotes tolerance of VHL loss in renal epithelia, which may promote the development of renal carcinoma...
  5. pmc Hypoxia and senescence: the impact of oxygenation on tumor suppression
    Scott M Welford
    Department of Radiation Oncology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, BRB 325, Cleveland, OH 44106, USA
    Mol Cancer Res 9:538-44. 2011
    ..Hypoxia is particularly important in normal physiology to maintain the stem cell niche; but at the same time, hypoxic inhibition of an essential tumor suppressor response can theoretically contribute to cancer initiation...
  6. pmc Harnessing synthetic lethal interactions in anticancer drug discovery
    Denise A Chan
    Department of Radiation Oncology, University of California, San Francisco, California 94143 1331, USA
    Nat Rev Drug Discov 10:351-64. 2011
    ....
  7. pmc The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO
    Erinn B Rankin
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303 5152, USA
    Cell 149:63-74. 2012
    ..Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment...
  8. pmc Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes
    Cullen M Taniguchi
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford, California, USA
    Nat Med 19:1325-30. 2013
    ..Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms. ..
  9. pmc The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia-inducible factor 1 target gene and promotes survival and proliferation of VHL-deficient renal cancer cells
    Olga V Razorenova
    Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, California, USA
    Mol Cell Biol 34:739-51. 2014
    ..In addition, loss of ARC resulted in a dramatic reduction of RCC tumor growth in SCID mice in vivo. Thus, HIF-mediated increased expression of ARC in RCC can explain how loss of VHL can promote survival early in tumor formation. ..
  10. pmc MiR-210--micromanager of the hypoxia pathway
    Xin Huang
    Magee Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Trends Mol Med 16:230-7. 2010
    ....
  11. pmc Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth
    Adam J Krieg
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303 5152, USA
    Mol Cell Biol 30:344-53. 2010
    ..Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth...
  12. pmc DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response
    Rachel A Freiberg
    CCSR South, Room 1255, Department of Radiation Oncology, Stanford University, Stanford, CA 94305 5152, USA
    Mol Cell Biol 26:1598-609. 2006
    ....
  13. pmc Genome-wide analysis of p53 under hypoxic conditions
    Ester M Hammond
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94303 5152, USA
    Mol Cell Biol 26:3492-504. 2006
    ..This study defines a new role for residues 53 and 54 of p53 in regulating transrepression and demonstrates that 25-26 and 53-54 work in the same pathway to induce apoptosis through gene repression...
  14. ncbi Checking in on hypoxia/reoxygenation
    Rachel A Freiberg
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, California 94303 5152, USA
    Cell Cycle 5:1304-7. 2006
    ..In contrast, loss of a p53-mediated reoxygenation-induced G1 arrest does not correlate with increased sensitivity to hypoxia/reoxygenation...
  15. pmc Functional analysis of p53 binding under differential stresses
    Adam J Krieg
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA 94303 5152, USA
    Mol Cell Biol 26:7030-45. 2006
    ..Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios...
  16. pmc HIF1alpha delays premature senescence through the activation of MIF
    Scott M Welford
    Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA
    Genes Dev 20:3366-71. 2006
    ..Inhibition of MIF phenocopies loss of HIF1alpha. Our findings highlight a novel role for HIF1alpha under aerobic conditions, and identify MIF as a target responsible for this function...
  17. pmc Hif-1alpha regulates differentiation of limb bud mesenchyme and joint development
    Sylvain Provot
    Endocrine Unit, Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, MA 02114, USA
    J Cell Biol 177:451-64. 2007
    ..In addition, mutant mice show a striking impairment of joint development. Our study demonstrates a crucial, and previously unrecognized, role of Hif-1alpha in early chondrogenesis and joint formation...
  18. ncbi Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells
    Patrick D Sutphin
    Program in Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA
    Cancer Res 67:5896-905. 2007
    ....
  19. pmc Bringing H2AX into the angiogenesis family
    Erinn B Rankin
    Department of Radiation Oncology, Division of Radiation and Cancer Biology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303 5152, USA
    Cancer Cell 15:459-61. 2009
    ..Paradoxically, Economopoulou et al. recently reported that a DNA damage response protein, H2AX, promotes tumor growth and angiogenesis...
  20. pmc PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2
    Cullen M Taniguchi
    Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
    Sci Transl Med 6:236ra64. 2014
    ..Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures. ..

Research Grants30

  1. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013
    ..These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation. ..
  2. Mdig gene and histone demethylation in lung cancer
    Fei Chen; Fiscal Year: 2013
    ....
  3. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  4. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  5. MECHANISMS OF BREAST DEVELOPMENT AND CARCINOGENESIS
    Robert A Weinberg; Fiscal Year: 2013
    ..abstract_text> ..
  6. Role of the Y-Located TSPY Gene in Human Oncogenesis
    Yun Fai Chris Lau; Fiscal Year: 2013
    ..This project will shed important insights on how the Y-oncogene and X-tumor suppressor operate and how one can interfere or boost their actions respectively to treat prostate cancer. ..