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

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.

• Authors: Shahana Majid, Altaf A Dar, Varahram Shahryari, Hiroshi Hirata, Ardalan Ahmad, Sharanjot Saini, Yuichiro Tanaka, Angela V Dahiya, Rajvir Dahiya
• Journal: Cancer (Cancer) Vol. 116 Issue 1 Pg. 66-76 (Jan 01 2010) ISSN: 0008-543X [Print] United States
• PMID: 19885928 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2010 American Cancer Society.

Chemical References

• BTG3 protein, human
• Cell Cycle Proteins
• Histones
• Proteins
• Genistein

Topics

• Base Sequence
• Cell Cycle Proteins
• Cell Line, Tumor
• Chromatin Assembly and Disassembly (drug effects)
• DNA Methylation (drug effects)
• Genes, Tumor Suppressor
• Genistein (pharmacology)
• Histones (metabolism)
• Humans
• Male
• Molecular Sequence Data
• Prostatic Neoplasms (genetics)
• Proteins (genetics)