DNA methylation in aging, race and prostate cancer

Summary

Principal Investigator: Rajvir Dahiya
Abstract: The main goal of this proposal is to identify and characterize the epigenetic alterations that are involved in aging and race-related prostate cancer. Specific hypotheses: 1) The DNA methylation status of most frequently deleted genes [ERs, E-cadherin, CD44 and GSTPI (glutathione S-transferase pi)] will be different in aging and race-related prostate cancer. 2) Identification of novel DNA methylated genes will provide us the potential biomarkers of aging and race-related prostate cancer. 3) DNA methyltransferase, DNA demethylase and histone deacetylase activities will correspond to DNA methylation status in aging and race-related prostate cancer. Specific Aim number 1. To test the hypothesis that inactivation of ER genes by DNA methylation can be used as biomarkers for aging and race-related prostate cancer. We hypothesize that ERalpha and ERbeta are differentially expressed in different aging and race related prostate cancer. To test this hypothesis we will investigate the mRNA and protein expression of ER types (alpha and beta) in different stages and grades of prostate cancer. Protein expression of ERs will be analyzed by immunohistochemistry (for localization) and western blotting (for quantitation). RT-PCR (for screening) and northern blotting (for quantitation) will analyze Gene expression. DNA methylation will be analyzed by sodium bisulfite methylation techniques and confirm by direct DNA sequencing. Specific Aim number 2. To test the hypothesis that inactivation of E-cadherin, CD44 and GSTPI genes by DNA methylation can be used as biomarkers for aging and race-related prostate cancer. Based on our preliminary data and prior publications, E-cadherin, CD44 and GSTPI genes are most frequently inactivated by DNA methylation in prostate cancer. We hypothesize that the expression or inactivation of these genes will be different in aging and race- related prostate cancer. To test this hypothesis, we will first determine the protein expression of these genes in prostate cancer using immunohistochemistry (for localization), and western blotting (for quantitation). RNA expression will be analyzed by RT-PCR (for screening) and northern blotting (for quantitation). CpG methylation will be analyzed by sodium bisulfite methylation techniques and confirm by direct DNA sequencing. Specific Aim number 3. To test the hypothesis that identification of new DNA methylated genes by restriction landmark genomic scanning (RLGS) can be used as novel biomarkers for aging and race-related prostate cancer. We hypothesize that identification of novel genes that are inactivated by DNA methylation will be important in understanding the mechanisms of aging and race-related prostate cancer. To test this hypothesis, we will analyze new genes that are methylated in aging and race-related prostate cancer. We will use Restriction landmark genomic scanning for methylation (RLGS) to survey genome wide methylation alterations in aging and race-related prostate cancer and subsequently verify potentially hypermethylated gene loci using sodium bisulfite sequencing technique. Specific Aim number 4. To investigate the mechanisms of DNA methylation in aging and race-related prostate cancer. We hypothesize that DNA methyltransferase, DNA demethylase, histone deacetylase are responsible for regulation of DNA hypermethylation. To test this hypothesis, we will analyze DNA methyltransferase, DNA demethylase and histone deacetylase enzyme activity, mRNA and protein expression in different age and race related prostate cancer. Accomplishment of these experiments will demonstrate whether DNA methylated genes are involved in aging and race-related prostate cancer. This information can be used for better management of prostate cancer using DNA methylated genes as diagnostic or prognostic biomarkers.
Funding Period: 2002-07-15 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer
    Steven T Okino
    Department of Urology, San Francisco Veterans Affairs Medical Center 4150 Clement Street, San Francisco, CA 94121, USA
    Cancer Res 66:7420-8. 2006
  2. ncbi Epigenetic changes in prostate cancer: implication for diagnosis and treatment
    Long Cheng Li
    Department of Urology, Veterans Affairs Medical Center, and University of California San Francisco, 94121, USA
    J Natl Cancer Inst 97:103-15. 2005
  3. ncbi The E-cadherin -160 C/A polymorphism and prostate cancer risk in white and black American men
    Deepa Pookot
    Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, 94121, USA
    J Urol 176:793-6. 2006
  4. pmc Small dsRNAs induce transcriptional activation in human cells
    Long Cheng Li
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Proc Natl Acad Sci U S A 103:17337-42. 2006
  5. ncbi Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA
    Shinji Urakami
    Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA
    Clin Cancer Res 12:6989-97. 2006
  6. ncbi Polymorphisms of DNA repair genes are risk factors for prostate cancer
    Hiroshi Hirata
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, United States
    Eur J Cancer 43:231-7. 2007
  7. ncbi Chromatin changes on the GSTP1 promoter associated with its inactivation in prostate cancer
    Steven T Okino
    Department of Urology, San Francisco Veterans Affairs Medical Center and the University of California San Francisco, San Francisco, California 94121, USA
    Mol Carcinog 46:839-46. 2007
  8. ncbi Epigenetic modifications of RASSF1A gene through chromatin remodeling in prostate cancer
    Ken Kawamoto
    Department of Urology, Veterans Affairs Medical Center and University of California School of Medicine, San Francisco, California 94121, USA
    Clin Cancer Res 13:2541-8. 2007
  9. ncbi Epigenetics of prostate cancer
    Long Cheng Li
    Department of Urology, University of California San Francisco and Veterans Affairs Medical Center San Francisco, San Francisco, CA 94121, USA
    Front Biosci 12:3377-97. 2007
  10. ncbi Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity
    N Kikuno
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Oncogene 26:7647-55. 2007

Scientific Experts

  • Long Cheng Li
  • Makoto Ishikawa
  • Steven T Okino
  • Rajvir Dahiya
  • Shinji Urakami
  • Hideki Enokida
  • Hiroaki Shiina
  • Mikio Igawa
  • Yuichiro Tanaka
  • Hiroshi Hirata
  • Tatsuya Ogishima
  • Ken Kawamoto
  • Toshifumi Kawakami
  • Nobuyuki Kikuno
  • Masayuki Nakagawa
  • Masaharu Terashima
  • Christopher J Kane
  • Peter R Carroll
  • Julia E Breault
  • Yutaka Suehiro
  • Yuji Hinoda
  • Deepa Pookot
  • Takashi Tokizane
  • Leopoldo A Ribeiro-Filho
  • Naoko Okayama
  • Shahana Majid
  • Hong Zhao
  • Motoshi Kawahara
  • Masanori Kaneuchi
  • N Kikuno
  • Kazushi Shigeno
  • Tatsuaki Yoneda
  • Kirsten L Greene
  • Z Laura Tabatabai
  • Hirofumi Kishi
  • Masao Deguchi
  • Makoto Fujime
  • R Dahiya
  • H Hirata
  • D Pookot
  • Y Tanaka
  • K Kawamoto
  • S Majid
  • S Urakami
  • Robert F Place
  • M Igawa
  • Zhong Chen
  • Kaveh Vejdani
  • R F Place
  • H Shiina
  • Badrinath R Konety
  • Hideyasu Matsuyama
  • Katsusuke Naito
  • Hiroyuki Adachi
  • Masahiro Sasaki
  • Hideto Yamada
  • Laura Tabatabai
  • Norio Nonomura
  • William W Bassett
  • Ritsu Yamamoto
  • Akihiko Okuyama
  • Mukesh Verma
  • Satoshi Honda
  • Peter Carroll
  • William W Basset
  • Noriaki Sakuragi

Detail Information

Publications28

  1. ncbi Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer
    Steven T Okino
    Department of Urology, San Francisco Veterans Affairs Medical Center 4150 Clement Street, San Francisco, CA 94121, USA
    Cancer Res 66:7420-8. 2006
    ..This is the first report that shows that CYP1A1 is aberrantly hypermethylated in human prostate cancer and has an altered, inaccessible chromatin structure that suppresses its dioxin responsiveness...
  2. ncbi Epigenetic changes in prostate cancer: implication for diagnosis and treatment
    Long Cheng Li
    Department of Urology, Veterans Affairs Medical Center, and University of California San Francisco, 94121, USA
    J Natl Cancer Inst 97:103-15. 2005
    ..In this review, we examine the current literature on epigenetic changes in prostate cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease...
  3. ncbi The E-cadherin -160 C/A polymorphism and prostate cancer risk in white and black American men
    Deepa Pookot
    Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, 94121, USA
    J Urol 176:793-6. 2006
    ..We hypothesized that allelic variation at this site may be associated with racial differences in the incidence and severity of prostate cancer...
  4. pmc Small dsRNAs induce transcriptional activation in human cells
    Long Cheng Li
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Proc Natl Acad Sci U S A 103:17337-42. 2006
    ..These findings reveal a more diverse role for small RNA molecules in the regulation of gene expression than previously recognized and identify a potential therapeutic use for dsRNA in targeted gene activation...
  5. ncbi Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA
    Shinji Urakami
    Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA
    Clin Cancer Res 12:6989-97. 2006
    ..We hypothesized that combined methylation analysis of Wnt antagonist genes could serve as a panel of biomarkers for diagnosis, staging, and prognosis in renal cell carcinoma (RCC)...
  6. ncbi Polymorphisms of DNA repair genes are risk factors for prostate cancer
    Hiroshi Hirata
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, United States
    Eur J Cancer 43:231-7. 2007
    ..This is the first report on the studies of XPC and XRCC1 Arg194Trp polymorphisms in PC, and our present data suggest that XPC Lys939Gln and the T-A haplotype of XRCC1 Arg194Trp and Arg399Gln may be risk factors for PC in Japanese...
  7. ncbi Chromatin changes on the GSTP1 promoter associated with its inactivation in prostate cancer
    Steven T Okino
    Department of Urology, San Francisco Veterans Affairs Medical Center and the University of California San Francisco, San Francisco, California 94121, USA
    Mol Carcinog 46:839-46. 2007
    ..We conclude that, in the process of prostate carcinogenesis, activating histone modifications on GSTP1 are lost and the DNA becomes methylated and inaccessible resulting in transcriptional silencing...
  8. ncbi Epigenetic modifications of RASSF1A gene through chromatin remodeling in prostate cancer
    Ken Kawamoto
    Department of Urology, Veterans Affairs Medical Center and University of California School of Medicine, San Francisco, California 94121, USA
    Clin Cancer Res 13:2541-8. 2007
    ..The present study was designed to investigate the mechanisms of inactivation of the RASSF1A gene through the analysis of CpG methylation and histone acetylation and H3 methylation associated with the RASSF1A promoter region...
  9. ncbi Epigenetics of prostate cancer
    Long Cheng Li
    Department of Urology, University of California San Francisco and Veterans Affairs Medical Center San Francisco, San Francisco, CA 94121, USA
    Front Biosci 12:3377-97. 2007
    ..In this chapter, we examined the current literature regarding epigenetic changes in prostate cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease...
  10. ncbi Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity
    N Kikuno
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Oncogene 26:7647-55. 2007
    ..AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis...
  11. ncbi MDM2 SNP309 polymorphism as risk factor for susceptibility and poor prognosis in renal cell carcinoma
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA
    Clin Cancer Res 13:4123-9. 2007
    ..There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer...
  12. ncbi A dioxin-responsive enhancer 3' of the human CYP1A2 gene
    Steven T Okino
    Department of Urology, San Francisco Veterans Affairs Medical Center and UCSF, 4150 Clement Street, San Francisco, CA 94121, USA
    Mol Pharmacol 72:1457-65. 2007
    ..In summary, we identify a novel TCDD-responsive enhancer for CYP1A2. We were surprised to find that this enhancer is not conserved across species and is primarily human-specific...
  13. pmc Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer
    Hiroshi Hirata
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA
    J Urol 179:2020-4. 2008
    ..We hypothesized that mismatch repair gene polymorphism could be a risk factor for prostate cancer and p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms...
  14. ncbi Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection
    Shinji Urakami
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California, USA
    Clin Cancer Res 12:2109-16. 2006
    ..We hypothesized that combined methylation analysis of Wnt-antagonist genes could improve their use as a panel of biomarkers for diagnosing and staging of bladder cancers...
  15. ncbi Polymorphisms of DNA repair genes are associated with renal cell carcinoma
    Hiroshi Hirata
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA
    Biochem Biophys Res Commun 342:1058-62. 2006
    ..Our present data suggest that the XRCC1 399Gln allele may be linked to susceptibility for RCC...
  16. ncbi Plasma adiponectin and gastric cancer
    Makoto Ishikawa
    Department of Surgery, Division of Surgical Oncology, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 8655, Japan
    Clin Cancer Res 11:466-72. 2005
    ..Moreover, the circulating level of adiponectin has been reported to be inversely related to body mass index...
  17. ncbi Methylation of the gamma-catenin gene is associated with poor prognosis of renal cell carcinoma
    Julia E Breault
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Clin Cancer Res 11:557-64. 2005
    ..To test these hypotheses, we analyzed the CpG methylation status of the gamma-catenin gene and its correlation with clinical outcome in RCC...
  18. ncbi Increased heparanase expression is caused by promoter hypomethylation and up-regulation of transcriptional factor early growth response-1 in human prostate cancer
    Tatsuya Ogishima
    Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA
    Clin Cancer Res 11:1028-36. 2005
    ..We hypothesize that CpG hypomethylation in the heparanase promoter coupled with up-regulation of EGR1 levels may induce heparanase expression in human prostate cancer...
  19. ncbi Functional Loss of the gamma-catenin gene through epigenetic and genetic pathways in human prostate cancer
    Hiroaki Shiina
    Department of Urology, Shimane University School of Medicine, Izumo, Japan
    Cancer Res 65:2130-8. 2005
    ..The gamma-catenin mutation related to Bcl-2 overexpression has a significant effect on the pathogenesis of HRPC. This is the first report to characterize the epigenetic and genetic regulation of gamma-catenin in human prostate cancer...
  20. ncbi Ethnic group-related differences in CpG hypermethylation of the GSTP1 gene promoter among African-American, Caucasian and Asian patients with prostate cancer
    Hideki Enokida
    Department of Urology and Pathology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Int J Cancer 116:174-81. 2005
    ..Ours is the first study investigating GSTP1 methylation differences in PC among African-American, Caucasian and Asian...
  21. ncbi CpG methylation at promoter site -140 inactivates TGFbeta2 receptor gene in prostate cancer
    Hong Zhao
    Department of Urology, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California 94121, USA
    Cancer 104:44-52. 2005
    ..The authors of the current study hypothesized that CpG methylation of the TbetaRII promoter at the Sp1 binding site -140 mediates this loss of TbetaRII expression in prostate cancer...
  22. ncbi Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer
    Tatsuya Ogishima
    Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California, San Francisco, 4150 Clement Street, CA 94121, USA
    Oncogene 24:6765-72. 2005
    ..To our knowledge, this is the first study demonstrating that increased heparanase expression during the pathogenesis of bladder cancer is due to promoter hypomethylation and transcription factor EGR1...
  23. ncbi Cytochrome P450 1B1 is overexpressed and regulated by hypomethylation in prostate cancer
    Takashi Tokizane
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA
    Clin Cancer Res 11:5793-801. 2005
    ..We hypothesized that promoter/enhancer CpG methylation contributes to the regulation of CYP1B1 expression in human prostate tissue...
  24. ncbi WT1 and WT1-AS genes are inactivated by promoter methylation in ovarian clear cell adenocarcinoma
    Masanori Kaneuchi
    Department of Urology, University of California San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121, USA
    Cancer 104:1924-30. 2005
    ..The authors hypothesized that Wilms tumor suppressor 1 gene (WT1) sense and antisense (WT1-AS) expression and their promoter methylation status could characterize ovarian clear cell adenocarcinoma from ovarian serous adenocarcinoma...
  25. ncbi Multigene methylation analysis for detection and staging of prostate cancer
    Hideki Enokida
    Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA
    Clin Cancer Res 11:6582-8. 2005
    ..We hypothesize that a new method of multigene methylation analysis could be a good diagnostic and staging biomarker for prostate cancer...
  26. ncbi Smoking influences aberrant CpG hypermethylation of multiple genes in human prostate carcinoma
    Hideki Enokida
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA
    Cancer 106:79-86. 2006
    ..The authors hypothesized that smoking influences both progression and prognosis of PC through CpG hypermethylation of related genes...
  27. ncbi Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway
    Shinji Urakami
    Department of Urology 112F, Veterans Affairs Medical Center, and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Clin Cancer Res 12:383-91. 2006
    ..Wnt inhibitory factor-1 (Wif-1) was identified as one of the secreted antagonists that can bind Wnt protein. We hypothesize that Wif-1 plays an important role in bladder cancer pathogenesis...
  28. ncbi Toxic and chemopreventive ligands preferentially activate distinct aryl hydrocarbon receptor pathways: implications for cancer prevention
    Steven T Okino
    Department of Urology, San Francisco Veterans Affairs Medical Center and the University of California at San Francisco, San Francisco, California 94121, USA
    Cancer Prev Res (Phila) 2:251-6. 2009
    ..Our findings reveal that DIM and TCDD each elicit a unique pattern of change in pathways that control estrogen action; such patterns may determine if an AhR ligand has beneficial or adverse health effects...