Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer

Shahana Majid, Altaf A. Dar, Varahram Shahryari, Hiroshi Hirata, Ardalan Ahmad, Sharanjot Saini, Yuichiro Tanaka, Angela V. Dahiya, Rajvir Dahiya

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

BACKGROUND: B-cell translocation gene 3 (BTG3/ANA/APRO4) is a candidate tumor suppressor gene in some malignancies.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. METHODS: Prostate cancer and normal cell lines were treated with different doses of genistein and 5-aza-2′-deoxycytidine (5Aza-C). BTG3 messenger ribonucleic acid (mRNA) expression was determined by quantitative real-time polymerase chain reaction in tissues and cell lines. Bisulfate-modified polymerase chain reaction, cloning and sequencing were used to examine promoter methylation in tumor samples and cell lines. Enzyme activity/inhibition assays were done to check the effect of genistein and 5Aza-C on DNA methyltransferases. ChIP assay was performed to analyze chromatin modifications caused by genistein treatment. RESULTS: BTG3 mRNA expression was down-regulated in cancer tissues and cells. Genistein and 5Aza-C induced BTG3 mRNA expression in all PC cell lines. Complete methylation of BTG3 promoter in tumor samples and cancer cell lines was observed. Genistein and 5Aza-C treatment significantly decreased promoter methylation, reactivating BTG3 expression. Genistein and 5Aza-C increased levels of acetylated histones 3, 4, histone 3 dimethylated at lysine 4, histone 3 trimethylated at lysine 4, and RNA polymerase II, decreased DNA methyl transferase and methyl-binding domain protein 2 activity, and increased histone acetyl transferase (HAT) activity. CONCLUSIONS: This is the first report to show that BTG3 is silenced in prostate cancer and can be reactivated by genistein-induced promoter demethylation and active histone modification. Genistein showed similar effects to that of 5Aza-C, which is currently undergoing phase 2 clinical trials as a treatment for prostate cancer. Because genistein is a natural, nontoxic, and dietary isoflavone, these results indicate that genistein is a novel, advantageous therapeutic agent for treating prostate cancer.

Original languageEnglish (US)
Pages (from-to)66-76
Number of pages11
JournalCancer
Volume116
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Keywords

  • BTG3
  • DNA methylation
  • Genistein
  • Histone modification
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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