DE NOVO DNA METHYLATION IN BLADDER CANCER

Summary

Principal Investigator: GANGNING NONE LIANG
Abstract: DESCRIPTION (provided by applicant): The objectives of this grant, which has been funded for almost 30 years, are to understand the genetic and epigenetic basis of human bladder cancer. We have defined the existence of two molecular pathways for the genesis of bladder cancer (UC) in which superficial (Ta/T1) tumors, which frequently recur, are distinct from more aggressive tumors at the molecular level. We have also shown profound epigenetic alterations which occur during bladder carcinogenesis and want to continue our studies by using more global approaches to define key genes which may play a role in this prevalent but understudied disease. In the next five year period of the grant, we will use a series of eight hypermethylation markers to complete the examination of DNA in urine sediments obtained from individuals with low grade tumors to determine whether we can detect the frequent recurrences of these tumors. We shall also complete the analysis of DNA from healthy individuals of different ages to determine whether age-related changes in DNA methylation can be detected in urine sediments. Secondly, using high-throughput approaches on the Illumina platform, we have observed a hypomethylation phenotype not seen in the apparently normal urothelium but particularly prevalent in superficial tumors and less frequently in more invasive tumors. This hypomethylation is seen in the vicinity of transcription start sites and might play a role in ectopic gene activation in tumors. In Specific Aims 3 and 4 we will determine the functional significance of these changes by analyzing directly whether methylation of non- CpG island regions which constitute the bulk of the hypomethylation phenotype might be involved in gene activation and have chromatin properties associated with active genes. Finally, in Specific Aim 5 we will take advantage of ongoing clinical trials in which patients with myelodysplastic syndrome are being treated with the hypomethylating drug 5-azacytidine (5-aza-CR). Since we can easily and non-invasively obtain urine sediments from these patients, we can directly test the hypothesis that systemic administration of hypomethylating drugs leads to demethylation of bladder urothelial cells which may have implications in the future for treatment of this disease.
Funding Period: 2000-03-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival
    Gerda Egger
    Norris Comprehensive Cancer Center, Departments of Urology and Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA
    Proc Natl Acad Sci U S A 103:14080-5. 2006
  2. pmc DNA methylation directly silences genes with non-CpG island promoters and establishes a nucleosome occupied promoter
    Han Han
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
    Hum Mol Genet 20:4299-310. 2011
  3. pmc Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells
    Claudia Andreu-Vieyra
    Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
    Mol Cell Biol 31:4648-62. 2011
  4. ncbi Functions of DNA methylation: islands, start sites, gene bodies and beyond
    Peter A Jones
    USC Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, California 90089 99176, USA
    Nat Rev Genet 13:484-92. 2012
  5. pmc Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules
    Theresa K Kelly
    Department of Urology, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Genome Res 22:2497-506. 2012
  6. pmc Functional DNA demethylation is accompanied by chromatin accessibility
    Kurinji Pandiyan
    Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
    Nucleic Acids Res 41:3973-85. 2013
  7. pmc Reprogramming of the human intestinal epigenome by surgical tissue transposition
    Fides D Lay
    Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Genome Res 24:545-53. 2014
  8. pmc Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue
    Erika M Wolff
    Department of Urology, USC Epigenome Center, and Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089, USA
    Cancer Res 70:8169-78. 2010
  9. pmc DNA methylation and cellular reprogramming
    Daniel D De Carvalho
    Department of Urology, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    Trends Cell Biol 20:609-17. 2010
  10. pmc Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort
    Aimee M Near
    Cancer Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
    Fertil Steril 95:40-5. 2011

Research Grants

Detail Information

Publications21

  1. pmc Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival
    Gerda Egger
    Norris Comprehensive Cancer Center, Departments of Urology and Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA
    Proc Natl Acad Sci U S A 103:14080-5. 2006
    ..Our data suggest that DNMT1 might be essential for maintenance of DNA methylation, proliferation, and survival of cancer cells...
  2. pmc DNA methylation directly silences genes with non-CpG island promoters and establishes a nucleosome occupied promoter
    Han Han
    Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA
    Hum Mol Genet 20:4299-310. 2011
    ....
  3. pmc Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells
    Claudia Andreu-Vieyra
    Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA
    Mol Cell Biol 31:4648-62. 2011
    ..This allows the recruitment of histone modifiers, chromatin remodelers, and ultimately gene activation. The "receptive" state described here could help explain AR signaling activation under very low ligand concentrations...
  4. ncbi Functions of DNA methylation: islands, start sites, gene bodies and beyond
    Peter A Jones
    USC Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, California 90089 99176, USA
    Nat Rev Genet 13:484-92. 2012
    ..Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer...
  5. pmc Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules
    Theresa K Kelly
    Department of Urology, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Genome Res 22:2497-506. 2012
    ....
  6. pmc Functional DNA demethylation is accompanied by chromatin accessibility
    Kurinji Pandiyan
    Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
    Nucleic Acids Res 41:3973-85. 2013
    ....
  7. pmc Reprogramming of the human intestinal epigenome by surgical tissue transposition
    Fides D Lay
    Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Genome Res 24:545-53. 2014
    ....
  8. pmc Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue
    Erika M Wolff
    Department of Urology, USC Epigenome Center, and Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089, USA
    Cancer Res 70:8169-78. 2010
    ..In addition, an epithelium-wide epigenetic defect in bladders with cancer might contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise...
  9. pmc DNA methylation and cellular reprogramming
    Daniel D De Carvalho
    Department of Urology, University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    Trends Cell Biol 20:609-17. 2010
    ..Elucidation of the epigenetic changes taking place during cellular reprogramming will enhance our understanding of stem cell biology and facilitate therapeutic applications...
  10. pmc Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort
    Aimee M Near
    Cancer Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
    Fertil Steril 95:40-5. 2011
    ..To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism and the PROGINS allele...
  11. 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
    ....
  12. pmc Chromatin, cancer and drug therapies
    Connie C Cortez
    Department of Urology, University of Southern California, Los Angeles, CA 90089 9181, USA
    Mutat Res 647:44-51. 2008
    ..Progress has been made in the treatment of hematological malignancies and some solid tumors. As the knowledge of how chromatin regulates gene expression is enhanced, improvements in the treatment of cancer can be made...
  13. ncbi The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2
    Jeffrey M Friedman
    Department of Urology, Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Cancer Res 69:2623-9. 2009
    ..We conclude that miR-101 may be a potent tumor suppressor by altering global chromatin structure through repression of EZH2...
  14. pmc DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation
    Tina Branscombe Miranda
    Department of Urology, USC Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
    Mol Cancer Ther 8:1579-88. 2009
    ..This suggests that there is a homeostatic mechanism that returns the histone modifications to their "ground state" after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors...
  15. pmc Epigenetics in cancer
    Shikhar Sharma
    Department of Urology, Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center Keck School of Medicine, University of Southern California, Los Angeles, CA 90089 9181, USA
    Carcinogenesis 31:27-36. 2010
    ....
  16. pmc Rethinking how DNA methylation patterns are maintained
    Peter A Jones
    Peter A Jones and Gangning Liang are at the Department of Urology, Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089 9181, USA
    Nat Rev Genet 10:805-11. 2009
    ....
  17. pmc Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer
    Erika M Wolff
    Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
    PLoS Genet 6:e1000917. 2010
    ..These data show that, in addition to contributing to chromosomal instability, hypomethylation of LINE-1s can alter the functional transcriptome and plays a role not only in human disease but also in disease predisposition...
  18. pmc S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth
    Jody C Chuang
    Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Mol Cancer Ther 9:1443-50. 2010
    ..We also show that S110 is effective by both i.p. and s.c. deliveries. S110 therefore is a promising new agent that acts similarly to 5-Aza-CdR and has better stability and less toxicity...
  19. ncbi A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence
    Sheng Fang Su
    Authors Affiliations Departments of Urology and Preventive Medicine Program in Genetic, Molecular, and Cellular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles and Department of Urology, School of Medicine, University of Stanford, Stanford, California
    Clin Cancer Res 20:1978-89. 2014
    ..Some urine markers have been used to help detect bladder tumors; however, their use in longitudinal tumor recurrence surveillance has yet to be established...

Research Grants30

  1. Multiscale Mathematical Modeling of Cancer Progression
    Vito Quaranta; Fiscal Year: 2013
    ..Finally, we will continue education/outreach efforts, e.g., hands-on cancer modeling workshops, to attract physical and biological scientists, especially the brightest of the new generations. ..
  2. Folate and PSMA Interact to Regulate DNA Methylation and Prostate Carcinogenesis
    DENISE SUSAN O'KEEFE; Fiscal Year: 2013
    ....
  3. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  4. NUCLEAR STRUCTURE AND GENE EXPRESSION
    Janet L Stein; Fiscal Year: 2013
    ..abstract_text> ..