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

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

Fingerprint

Histone Code
decitabine
Genistein
Tumor Suppressor Genes
Prostatic Neoplasms
B-Lymphocytes
Genes
Histones
Methylation
Cell Line
RNA
Transferases
Lysine
Neoplasms
Isoflavones
RNA Polymerase II
DNA
Methyltransferases
Therapeutics
Tumor Cell Line

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer. / Majid, Shahana; Dar, Altaf A.; Shahryari, Varahram; Hirata, Hiroshi; Ahmad, Ardalan; Saini, Sharanjot; Tanaka, Yuichiro; Dahiya, Angela V.; Dahiya, Rajvir.

In: Cancer, Vol. 116, No. 1, 01.01.2010, p. 66-76.

Research output: Contribution to journalArticle

Majid, S, Dar, AA, Shahryari, V, Hirata, H, Ahmad, A, Saini, S, Tanaka, Y, Dahiya, AV & Dahiya, R 2010, 'Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer', Cancer, vol. 116, no. 1, pp. 66-76. https://doi.org/10.1002/cncr.24662
Majid, Shahana ; Dar, Altaf A. ; Shahryari, Varahram ; Hirata, Hiroshi ; Ahmad, Ardalan ; Saini, Sharanjot ; Tanaka, Yuichiro ; Dahiya, Angela V. ; Dahiya, Rajvir. / Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer. In: Cancer. 2010 ; Vol. 116, No. 1. pp. 66-76.
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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.",
keywords = "BTG3, DNA methylation, Genistein, Histone modification, Prostate cancer",
author = "Shahana Majid and Dar, {Altaf A.} and Varahram Shahryari and Hiroshi Hirata and Ardalan Ahmad and Sharanjot Saini and Yuichiro Tanaka and Dahiya, {Angela V.} and Rajvir Dahiya",
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T1 - Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer

AU - Majid, Shahana

AU - Dar, Altaf A.

AU - Shahryari, Varahram

AU - Hirata, Hiroshi

AU - Ahmad, Ardalan

AU - Saini, Sharanjot

AU - Tanaka, Yuichiro

AU - Dahiya, Angela V.

AU - Dahiya, Rajvir

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

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KW - DNA methylation

KW - Genistein

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