Genistein cooperates with the histone deacetylase inhibitor vorinostat to induce cell death in prostate cancer cells

• Type of Material: Article
• Authors: Cornel J. Philip, Emory University; Christopher K. Giardina, Emory University; Birdal Bilir, Emory University; David J Cutler, Emory University; Yu-Heng Lai, Emory University; Omer Kucuk, Emory University; Carlos S Moreno, Emory University
• Language: English
• Date: 2012-04-11
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Phillip et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.biomedcentral.com/1471-2407/12/145
• Title of Journal or Parent Work: BMC Cancer
• ISSN: 1471-2407
• Volume: 12
• Issue: 145
• Start Page: 1
• End Page: 11
• Grant/Funding Information: Grant support: National Cancer Institute 2R01 CA 106826 (C.S. Moreno), Research Supplements to Promote Diversity in Health-Related Research grant R01CA106826-06 S1 (C.J. Phillip).; In addition, this research was supported in part by funds from Georgia Cancer Coalition.; Omer Kucuk is a Distinguished Scholar of Georgia Cancer Coalition, and Chris Giardina is Georgia Cancer Coalition Carpenter Fellow.
• Keywords: Epigenetics; Soy; Natural compounds; Prostate cancer; Apoptosis
• Research Categories: Biology, Molecular; Biology, Genetics; Health Sciences, Pathology

Abstract

Background Among American men, prostate cancer is the most common, non-cutaneous malignancy that accounted for an estimated 241,000 new cases and 34,000 deaths in 2011. Previous studies have suggested that Wnt pathway inhibitory genes are silenced by CpG hypermethylation, and other studies have suggested that genistein can demethylate hypermethylated DNA. Genistein is a soy isoflavone with diverse effects on cellular proliferation, survival, and gene expression that suggest it could be a potential therapeutic agent for prostate cancer. We undertook the present study to investigate the effects of genistein on the epigenome of prostate cancer cells and to discover novel combination approaches of other compounds with genistein that might be of translational utility. Here, we have investigated the effects of genistein on several prostate cancer cell lines, including the ARCaP-E/ARCaP-M model of the epithelial to mesenchymal transition (EMT), to analyze effects on their epigenetic state. In addition, we investigated the effects of combined treatment of genistein with the histone deacetylase inhibitor vorinostat on survival in prostate cancer cells. Methods Using whole genome expression profiling and whole genome methylation profiling, we have determined the genome-wide differences in genetic and epigenetic responses to genistein in prostate cancer cells before and after undergoing the EMT. Also, cells were treated with genistein, vorinostat, and combination treatment, where cell death and cell proliferation was determined. Results Contrary to earlier reports, genistein did not have an effect on CpG methylation at 20 μM, but it did affect histone H3K9 acetylation and induced increased expression of histone acetyltransferase 1 (HAT1). In addition, genistein also had differential effects on survival and cooperated with the histone deacteylase inhibitor vorinostat to induce cell death and inhibit proliferation. Conclusion Our results suggest that there are a number of pathways that are affected with genistein and vorinostat treatment such as Wnt, TNF, G2/M DNA damage checkpoint, and androgen signaling pathways. In addition, genistein cooperates with vorinostat to induce cell death in prostate cancer cell lines with a greater effect on early stage prostate cancer.