Genistein and Prostate Cancer

Summary

Principal Investigator: Rajvir Dahiya
Abstract: DESCRIPTION (provided by applicant): The main goal of this proposal is to investigate whether genistein inhibits prostate cancer growth through epigenetic pathways. The rationale for this project is that Western men have a 5-6 fold higher incidence of prostate cancer than Asians. One reason for this discrepancy may be the high soy diet (genistein) consumed by Asians. We hypothesize that genistein inhibits prostate cancer growth through epigenetic pathways. Specific Aim # 1. To investigate whether genistein can suppress prostate cancer growth through cell cycle arrest, cyclin genes and apoptosis. Based on the published literature and preliminary data, we lypothesize that genistein will inhibit prostate cancer cell growth in vitro. We will investigate whether genistein alone or in combination with demethylating agent (5-'-aza-2-deoxycytidine (5-AZA-C) and histone deacetylase inhibitor (trichostatin (TSA) can inhibit prostate cancer growth in vitro. A panel of human prostate cell lines will be studies for cell proliferation, cell cycle, cyclin genes and apoptosis. Specific Aim # 2. To investigate the molecular mechanisms of genistein action through epigenetic pathways. Based on our preliminary data, we hypothesize that genistein inhibits prostate cancer growth through modulation of epigenetic events, such as DNA methylation and histone acetylation. To test this hypothesis, we will analyze: 1) Global methylation and enzymatic activity of DNA methyltransferase (DNMT) using radiolabeled S- adenosylmethionine (SAM) assays. 2) Promoter methylation of candidate genes using bisulfite modification of DNA based techniques. 3) Alterations in gene-specific histone acetylation using ChIP assay, and enzymatic activities of histone acetyl transferases (HATs). 4) Histone deacetylase (HDACs) analysis using biochemical assays. 5). Alterations in mRNA expression of genes that encode enzymes participating in DNA methylation and histone acetylation including DNMTs, demethylases, HATs, HDACs using RT-PCR and northern blot assays. 6) To analyze transcription factors which mediate the effects of genistein on prostate cancer. Specific Aim # 3. To investigate whether genistein has anti-tumor effects through reversal of epigenetic pathways in prostate cancer using an in vivo system. Based on the published literature, genistein or demethylating agents have anti-proliferative effects on various cancers. We hypothesize that genistein will inhibit prostate cancer growth through reversal of epigenetic pathways. Studies will be conducted in athymic nude mice implanted with androgen-responsive LNCaP and androgen nonresponsive DuPro prostate cancer cells. Mice will be fed a diet supplemented with genistein, or a combination of genistein with 5-AZA-C or TSA. The following experiments will be conducted: 1) Determine the in vivo anti-tumor effects of genistein and in combination with 5-AZA-C or TSA. 2) To evaluate expression of steroid receptor genes and tumor suppressor genes at the mRNA and protein levels using Northern blot, and Western blotting analysi respectively. 3) To analyze whether genistein treatment can modulate global and candidate gene methylation in tumor tissue using a radiolabeled SAM assay and bisulfite modified genomic sequencing techniques respectively. 4) To analyze, in tumor tissue, gene-specific histone acetylation using ChIP assay and the enzymatic activities of HATs and HDACs using biochemical assays. Accomplishment of these experiments will demonstrate whether epigenetic events are modulated by genistein and provide rationale for a clinical trial of genistein alone or in combination with other epigenetic modulators for the treatment or prevention of prostate cancer.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. 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
  2. pmc MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California, USA
    Cancer 116:5637-49. 2010
  3. ncbi Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function
    Shashwati Basak
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    Mol Cancer Ther 7:3195-202. 2008
  4. ncbi Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells
    Nobuyuki Kikuno
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121, USA
    Int J Cancer 123:552-60. 2008
  5. ncbi Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA
    Cancer Res 68:2736-44. 2008
  6. ncbi DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines
    Ken Kawamoto
    Department of Urology, Veterans Affairs Medical Center and University of California School of Medicine, San Francisco, CA 94121, USA
    Int J Cancer 123:535-42. 2008
  7. 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
  8. pmc MicroRNA-373 induces expression of genes with complementary promoter sequences
    Robert F Place
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Proc Natl Acad Sci U S A 105:1608-13. 2008
  9. 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
  10. 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

Scientific Experts

  • Rajvir Dahiya
  • Hiroshi Hirata
  • Shahana Majid
  • Nobuyuki Kikuno
  • Yuichiro Tanaka
  • Ken Kawamoto
  • Yuji Hinoda
  • Koji Ueno
  • Soichiro Yamamura
  • Sharanjot Saini
  • Deepa Pookot
  • Varahram Shahryari
  • Z Laura Tabatabai
  • Kazumori Kawakami
  • Yutaka Suehiro
  • Robert F Place
  • Steven T Okino
  • Yi Chen
  • Altaf A Dar
  • Nobuhisa Ishii
  • Koichi Nakajima
  • Guoren Deng
  • M S Zaman
  • Shashwati Basak
  • Emily J Noonan
  • Masayuki Nakagawa
  • K Ueno
  • Jan Liu
  • Mohd Saif Zaman
  • Y Chen
  • V Shahryari
  • Gaurav Khatri
  • Angela V Dahiya
  • Jared M Whitson
  • H Hirata
  • Ardalan E Ahmad
  • S Majid
  • Mikio Igawa
  • Y Tanaka
  • Hideki Enokida
  • Shinji Urakami
  • N Kikuno
  • Y Hinoda
  • K Singh
  • Z L Tabatabai
  • Shranjot Saini
  • Mohd S Zaman
  • S O Suh
  • J Liu
  • Ardalan Ahmad
  • G Khatri
  • G Deng
  • S Saini
  • Hong Zhao
  • Long C Li
  • Steve T Okino
  • Jason Nelles
  • Naoko Okayama
  • Long Cheng Li
  • Emily Noonan
  • Hiroaki Shiina
  • R F Place
  • H Shiina
  • M Igawa
  • S Urakami
  • K Kawamoto
  • Linda C Quattrochi
  • Mieko Iwahashi
  • Zhong Chen
  • Toshifumi Kawakami
  • D Pookot

Detail Information

Publications28

  1. 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...
  2. pmc MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California, USA
    Cancer 116:5637-49. 2010
    ..In this study, the authors demonstrated that miRNA-205 (miR-205) induced the expression the interleukin (IL) tumor suppressor genes IL24 and IL32 by targeting specific sites in their promoters...
  3. ncbi Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function
    Shashwati Basak
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    Mol Cancer Ther 7:3195-202. 2008
    ..Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90...
  4. ncbi Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells
    Nobuyuki Kikuno
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121, USA
    Int J Cancer 123:552-60. 2008
    ..These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer...
  5. ncbi Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA
    Cancer Res 68:2736-44. 2008
    ..Altogether, our data provide new insights into the epigenetic mechanism of the action of genistein that may contribute to the chemopreventive activity of this dietary isoflavone and have important implications for epigenetic therapy...
  6. ncbi DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines
    Ken Kawamoto
    Department of Urology, Veterans Affairs Medical Center and University of California School of Medicine, San Francisco, CA 94121, USA
    Int J Cancer 123:535-42. 2008
    ..This is the first report indicating that aberrant DNA methylation and histone modifications work together to silence the sFRP2 gene in RCC cells...
  7. 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...
  8. pmc MicroRNA-373 induces expression of genes with complementary promoter sequences
    Robert F Place
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Proc Natl Acad Sci U S A 105:1608-13. 2008
    ..In conclusion, we have identified a miRNA that targets promoter sequences and induces gene expression. These findings reveal a new mode by which miRNAs may regulate gene expression...
  9. 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...
  10. 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...
  11. 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...
  12. ncbi Wnt antagonist DKK1 acts as a tumor suppressor gene that induces apoptosis and inhibits proliferation in human renal cell carcinoma
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
    Int J Cancer 128:1793-803. 2011
    ..In conclusion, this is the first report to show that DKK1 expression is epigenetically silenced in kidney cancer and its reexpression induces apoptosis and cell cycle arrest in RCC...
  13. pmc The functional significance of microRNA-145 in prostate cancer
    M S Zaman
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA, USA
    Br J Cancer 103:256-64. 2010
    ..Recent studies have shown aberrant expression of miRNAs in prostate cancer tissues and cell lines. On the basis of miRNA microarray data, we found that miR-145 is significantly downregulated in prostate cancer...
  14. pmc MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer
    Yi Chen
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California 94121, USA
    Cancer Prev Res (Phila) 4:76-86. 2011
    ..Genistein, a potential nontoxic chemopreventive agent, restores expression of ARHI and may be an important dietary therapeutic agent for treating prostate cancer...
  15. pmc Tumour suppressor microRNA-584 directly targets oncogene Rock-1 and decreases invasion ability in human clear cell renal cell carcinoma
    K Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Br J Cancer 104:308-15. 2011
    ..The purpose of this study was to identify new tumour suppressor microRNAs (miRs) in clear cell renal cell carcinoma (ccRCC), carry out functional analysis of their suppressive role and identify their specific target genes...
  16. ncbi IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma
    Koji Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA94121, USA
    Int J Cancer 129:2360-9. 2011
    ..This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis...
  17. pmc MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    Carcinogenesis 33:41-8. 2012
    ..In conclusion, our data suggest that the miR-1826 plays an important role as tumor suppressor via CTNNB1/MEK1/VEGFC downregulation in BC...
  18. ncbi Regulation of minichromosome maintenance gene family by microRNA-1296 and genistein in prostate cancer
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, CA, USA
    Cancer Res 70:2809-18. 2010
    ..The specific downregulation of oncogenes by miR may contribute to novel therapeutic approaches in the treatment of prostate cancer...
  19. ncbi Functional significance of Wnt inhibitory factor-1 gene in kidney cancer
    Kazumori Kawakami
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA
    Cancer Res 69:8603-10. 2009
    ..In conclusion, this is the first report documenting that the WIF-1 is downregulated by promoter methylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells...
  20. pmc Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-Cell translocation gene 3 in prostate cancer
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121, USA
    Cancer 116:66-76. 2010
    ..We report here that B-cell translocation gene 3 (BTG3) is transcriptionally down-regulated in prostate cancer and the mechanism of inactivation is through promoter hypermethylation...
  21. ncbi Wnt antagonist gene DKK2 is epigenetically silenced and inhibits renal cancer progression through apoptotic and cell cycle pathways
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA
    Clin Cancer Res 15:5678-87. 2009
    ..DKK2, a Wnt antagonist, is silenced in some cancers, although its function has not been investigated. We hypothesized that DKK2 may be epigenetically silenced and inhibits progression of renal cell carcinoma (RCC)...
  22. pmc Wnt antagonist gene polymorphisms and renal cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center, University of California at San Francisco, San Francisco, California, USA
    Cancer 115:4488-503. 2009
    ..Therefore, the authors of this report hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer...
  23. ncbi The bcl2 -938CC genotype has poor prognosis and lower survival in renal cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California 94121, USA
    J Urol 182:721-7. 2009
    ..Therefore, we investigated the polymorphism at the bcl2 -938C/A site and its effects on clinical characteristics in patients with renal cell carcinoma...
  24. pmc Double stranded-RNA-mediated activation of P21 gene induced apoptosis and cell cycle arrest in renal cell carcinoma
    Jared M Whitson
    University of California San Francisco, Department of Urology, San Francisco, CA 94121, USA
    Int J Cancer 125:446-52. 2009
    ..This is the first report that demonstrates dsRNA mediated gene activation in renal cell carcinoma and suggests that forced over-expression of p21 may lead to an increase in apoptosis through a survivin dependent mechanism...
  25. ncbi Bcl2 -938C/A polymorphism carries increased risk of biochemical recurrence after radical prostatectomy
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA
    J Urol 181:1907-12. 2009
    ..We investigated several polymorphisms related to the cell cycle and apoptosis, and their role in biochemical failure after radical prostatectomy...
  26. 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...
  27. pmc BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer
    Shahana Majid
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, CA 94121, USA
    Carcinogenesis 30:662-70. 2009
    ..Genistein being a natural, non-toxic, dietary isoflavone is effective in retarding the growth of RCC cells, making it a promising candidate for epigenetic therapy in renal carcinoma...
  28. pmc Tumor suppressor microRNA-493 decreases cell motility and migration ability in human bladder cancer cells by downregulating RhoC and FZD4
    Koji Ueno
    Departments of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA
    Mol Cancer Ther 11:244-53. 2012
    ..miR-493 also decreased binding of RhoC and Rock-1. miR-493 is a new tumor suppressor miRNA in bladder cancer and inhibits cell motility through downregulation of RhoC and FZD4...