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

BMC Cancer

Research Article

David J Cutler¹  Christopher K Giardina²  Cornel J Phillip²  Birdal Bilir²  Yu-Heng Lai³  Carlos S Moreno⁴  Omer Kucuk⁵ 

[1] Department of Human Genetics, Emory University, Atlanta, GA, USA;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, GA, USA;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, GA, USA;Winship Cancer Institute, Emory University, Atlanta, GA, USA;Winship Cancer Institute, Emory University, Atlanta, GA, USA;Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA;

关键词: Prostate cancer;    Soy;    Natural compounds;    Epigenetics;    Apoptosis;   

DOI  :  10.1186/1471-2407-12-145

 received in 2011-08-10, accepted in 2012-03-23,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundAmong 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.MethodsUsing 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.ResultsContrary 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.ConclusionOur 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.

【 授权许可】

Unknown   
© Phillip et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.