DNA Methyltrasferase Gene Expression in Colon Cancer

Summary

Principal Investigator: Stephen B Baylin
Abstract: We are studying how aberrantly silenced and DNA hypermethylated colorectal cancer (CRC) genes initiate early steps in CRC initiation and the molecular determinants of this gene silencing. The first aim focuses on SOX17, newly discovered to be DNA hypermethylated in ~90% of pre-invasive colon neoplasms. It encodes a protein essential for gut endoderm differentiation which inhibits, in the nucleus, Wnt pathway activation of [unreadable]-catenin mediated transcription. We are exploring whether direct SOX17 binding to gene promoters is involved, the genes targeted, and the role in CRC initiation. In our second aim, we explore mouse models for CRC evolution based on epigenetic loss of Hic1, a zinc finger, transcriptional repressor. Hic1 complexes with SIRT1 to directly suppress SIRT1 transcription. Hic1 deficient cells have decreased p53 function and resistance to DNA damage. Sirt1 may participate in silencing of DNA hypermethylated CRC genes. Hic1+/- knockout mice have increased colon Sirt1, abnormal colon crypt formation, and develop Hic1 negative, Sirt1 positive, colon polyps. Apc+/- (Min), Hic1+/- double het mice have markedly accelerated colon tumorigenesis. We are exploring how Sirt1 and other epigenetically silenced genes, may mediate this. The third aim utilizes siRNA and genetic approaches in primary, and/or immortalized, colonocytes, to explore how DNA hypermethylated mediated gene silencing, and the gene numbers involved, may help initiate CRC. Finally, we are asking whether increases in polycomb group (PcG) and associated proteins is a stress/survival response in CRC risk states, which may initiate abnormal epigenetic gene silencing. We explore a "molecular progression" model wherein these proteins recruit DNA methyltransferases (DNMT's) to gene promoters and the DNMT's, through transcriptional co- repression, may contribute to gene silencing prior to appearance of DNA methylation. We will time the appearance of these molecular events, including their localization to specific gene promoters, and will increase the protein complexes in DNMT deficient CRC cells to determine how genes are targeted for silencing. Relevance to Public Health: Our studies seek to identify how CRC risk states lead to abnormal silencing of genes. Reactivation of these genes holds promise for constructing prevention and treatment strategies for this disease.
Funding Period: 1991-04-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. ncbi De novo CpG island methylation in human cancer cells
    Kam Wing Jair
    The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA
    Cancer Res 66:682-92. 2006
  2. pmc Stress and the epigenetic landscape: a link to the pathobiology of human diseases?
    Sarah E Johnstone
    The Sidney Kimmel Cancer Research Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Suite 544, Baltimore, Maryland 21231 1000, USA
    Nat Rev Genet 11:806-12. 2010
  3. pmc Genomic and epigenomic integration identifies a prognostic signature in colon cancer
    Joo Mi Yi
    Department of Oncology, Johns Hopkins University, Baltimore, Maryland 20892 8110, USA
    Clin Cancer Res 17:1535-45. 2011
  4. pmc Loss of a single Hic1 allele accelerates polyp formation in Apc(Δ716) mice
    H P Mohammad
    The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA
    Oncogene 30:2659-69. 2011
  5. ncbi Role of nuclear architecture in epigenetic alterations in cancer
    H P Easwaran
    The Sidney Kimmel Cancer Research Center at Johns Hopkins University, Bunting Blaustein Cancer Research Building, Baltimore, Maryland 21231 1000, USA
    Cold Spring Harb Symp Quant Biol 75:507-15. 2010
  6. pmc Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
    Heather M O'Hagan
    Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Cancer Cell 20:606-19. 2011
  7. pmc DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes
    Eriko G Clements
    Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Nucleic Acids Res 40:4334-46. 2012
  8. pmc A DNA hypermethylation module for the stem/progenitor cell signature of cancer
    Hariharan Easwaran
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Johns Hopkins Medical Institutions, Baltimore, MD 21117, USA
    Genome Res 22:837-49. 2012
  9. pmc The cancer epigenome: its origins, contributions to tumorigenesis, and translational implications
    Stephen B Baylin
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA
    Proc Am Thorac Soc 9:64-5. 2012
  10. pmc The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes
    Y Cai
    Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
    Oncogene 33:2157-68. 2014

Research Grants

  1. METHYLATION OF THE CALCITONIN GENE IN HUMAN TUMORS
    Stephen B Baylin; Fiscal Year: 2013
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  3. CPG METHYLATION AND MUTATION
    Gerd P Pfeifer; Fiscal Year: 2013

Detail Information

Publications29

  1. ncbi De novo CpG island methylation in human cancer cells
    Kam Wing Jair
    The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA
    Cancer Res 66:682-92. 2006
    ..Our studies provide a new assay for de novo activity of DNMTs and data suggesting a potential role for DNMT1 in the initiation of promoter CpG island hypermethylation in human cancer cells...
  2. pmc Stress and the epigenetic landscape: a link to the pathobiology of human diseases?
    Sarah E Johnstone
    The Sidney Kimmel Cancer Research Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Suite 544, Baltimore, Maryland 21231 1000, USA
    Nat Rev Genet 11:806-12. 2010
    ..We emphasize the need to investigate epigenetic states in disease and links to stress and to consider how the knowledge gained through these studies may foster new means of disease prevention and management...
  3. pmc Genomic and epigenomic integration identifies a prognostic signature in colon cancer
    Joo Mi Yi
    Department of Oncology, Johns Hopkins University, Baltimore, Maryland 20892 8110, USA
    Clin Cancer Res 17:1535-45. 2011
    ..The importance of genetic and epigenetic alterations maybe in their aggregate role in altering core pathways in tumorigenesis...
  4. pmc Loss of a single Hic1 allele accelerates polyp formation in Apc(Δ716) mice
    H P Mohammad
    The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins, Johns Hopkins University, Baltimore, MD, USA
    Oncogene 30:2659-69. 2011
    ....
  5. ncbi Role of nuclear architecture in epigenetic alterations in cancer
    H P Easwaran
    The Sidney Kimmel Cancer Research Center at Johns Hopkins University, Bunting Blaustein Cancer Research Building, Baltimore, Maryland 21231 1000, USA
    Cold Spring Harb Symp Quant Biol 75:507-15. 2010
    ..We emphasize the need for further studies to elucidate the direct relationship between nuclear structure alterations and aberrant epigenetic patterns in cancers...
  6. pmc Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
    Heather M O'Hagan
    Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Cancer Cell 20:606-19. 2011
    ..Thus, oxidative damage induces formation and relocalization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing...
  7. pmc DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes
    Eriko G Clements
    Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Nucleic Acids Res 40:4334-46. 2012
    ....
  8. pmc A DNA hypermethylation module for the stem/progenitor cell signature of cancer
    Hariharan Easwaran
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Johns Hopkins Medical Institutions, Baltimore, MD 21117, USA
    Genome Res 22:837-49. 2012
    ..Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions...
  9. pmc The cancer epigenome: its origins, contributions to tumorigenesis, and translational implications
    Stephen B Baylin
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA
    Proc Am Thorac Soc 9:64-5. 2012
    ..We can use all of this basic information for translational purposes in terms of deriving biomarkers for cancer risk states and detection and therapeutic strategies...
  10. pmc The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes
    Y Cai
    Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
    Oncogene 33:2157-68. 2014
    ..Since CHD4 has ATPase activity, our data identify CHD4 as a potentially novel drug target in cancer. ..
  11. ncbi Novel methylation biomarker panel for the early detection of pancreatic cancer
    Joo Mi Yi
    Authors Affiliations Departments of Oncology, Surgery, Urology, and Mechanic Engineering, Johns Hopkins University Department of Biomedical Engineering, Johns Hopkins School of Medicine Department of Pathology, The Sol Goldman Pancreatic Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland MDxHealth, Ghent, Belgium and Research Institute, Dongnam Institute of Radiological and Medical Sciences DIRAMS, Busan, South Korea
    Clin Cancer Res 19:6544-55. 2013
    ..Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer...
  12. pmc A recombinant reporter system for monitoring reactivation of an endogenously DNA hypermethylated gene
    Ying Cui
    Authors Affiliations Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    Cancer Res 74:3834-43. 2014
    ....
  13. pmc Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus
    Hariharan P Easwaran
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
    Cancer Res 70:8015-24. 2010
    ..These findings have important implications for understanding relationships between nuclear organization and gene expression patterns in cancer...
  14. pmc Mapping networks of protein-mediated physical interactions between chromatin elements
    Vijay K Tiwari
    Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    Curr Protoc Mol Biol . 2010
    ..Thus, the 6C assay provides a useful tool to address the role of specific proteins in nuclear organization and to advance our understanding about the relation of chromatin higher-order organization and transcriptional regulation...
  15. pmc PcG proteins, DNA methylation, and gene repression by chromatin looping
    Vijay K Tiwari
    Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland, USA
    PLoS Biol 6:2911-27. 2008
    ..The loops associate with a poised, low transcription state in EC cells and, with the addition of DNA methylation, completely repressed transcription in adult cancer cells...
  16. ncbi Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation
    Angela H Ting
    Program in Cellular and Molecular Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA
    Cancer Res 66:729-35. 2006
    ..These observations suggest that human cancer cells may differ in their reliance on DNMT1 for maintaining DNA methylation...
  17. ncbi Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state
    Kelly M McGarvey
    Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA
    Cancer Res 66:3541-9. 2006
    ..This finding has important implications for the translational goal of reactivating aberrantly silenced cancer genes as a therapeutic maneuver...
  18. ncbi hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site
    Rebekah L Zinn
    Sidney Kimmel Comprehensive Cancer Center and Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Cancer Res 67:194-201. 2007
    ....
  19. pmc The epigenomics of cancer
    Peter A Jones
    Department of Urology, Biochemistry, and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
    Cell 128:683-92. 2007
    ....
  20. pmc Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes
    Yi Huang
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA
    Proc Natl Acad Sci U S A 104:8023-8. 2007
    ..We thus define important new agents for reversing aberrant repression of gene transcription...
  21. ncbi DNA methylation and complete transcriptional silencing of cancer genes persist after depletion of EZH2
    Kelly M McGarvey
    The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA
    Cancer Res 67:5097-102. 2007
    ..These results suggest that EZH2 can modulate transcription of basally expressed genes but not silent genes that are densely DNA methylated...
  22. pmc Comparing the DNA hypermethylome with gene mutations in human colorectal cancer
    Kornel E Schuebel
    Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
    PLoS Genet 3:1709-23. 2007
    ....
  23. pmc A requirement for DICER to maintain full promoter CpG island hypermethylation in human cancer cells
    Angela H Ting
    Genomic Medicine Institute, Lerner Research Institute, Cleveland, Ohio, USA
    Cancer Res 68:2570-5. 2008
    ..This reactivation is associated with a dramatic loss of localized promoter DNA hypermethylation. Thus, intact DICER is required to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in human cancer cells...
  24. pmc Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer
    Wei Zhang
    Division of Cancer Biology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA
    Cancer Res 68:2764-72. 2008
    ....
  25. pmc Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis
    Timothy A Chan
    Cancer Biology Program, The Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, United States of America
    PLoS Med 5:e114. 2008
    ..We hypothesize that key tumor suppressor genes in cancer may be subject to mutation or hypermethylation...
  26. pmc Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells
    Kelly M McGarvey
    Divisions of Cancer Biology, The Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21231, USA
    Cancer Res 68:5753-9. 2008
    ..Our data have great relevance for the increasing interest in reexpression of DNA-hypermethylated genes for the treatment of cancer...
  27. pmc Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors
    Joo Mi Yi
    Cancer Biology Division, Johns Hopkins Kimmel Cancer Center, USA
    Cancer Res 68:8094-103. 2008
    ..Our findings provide additional insight for the dynamics of aberrant DNA methylation associated with aberrant gene silencing in human tumors...
  28. pmc Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance
    Hariharan Easwaran
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
    Mol Cell 54:716-27. 2014
    ..In this review, we discuss the possible role of epigenetic abnormalities as well as genetic alterations in such dynamics and in the creation of cellular heterogeneity in cancers of all types. ..

Research Grants30

  1. METHYLATION OF THE CALCITONIN GENE IN HUMAN TUMORS
    Stephen B Baylin; Fiscal Year: 2013
    ..We investigate whether this change can foster cancer initiation and the molecular mechanisms though which it arises. ..
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  3. CPG METHYLATION AND MUTATION
    Gerd P Pfeifer; Fiscal Year: 2013
    ..In parallel, we will study molecular pathways involving the Polycomb repression complex that might operate during tumor progression to promote hypermethylation of CpG islands in malignant tissue. ..