Genistein Induces the p21WAF1/CIP1 and p16INK4a Tumor Suppressor Genes in Prostate Cancer Cells by Epigenetic Mechanisms Involving Active Chromatin Modification

Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.
Cancer Research (Impact Factor: 9.33). 05/2008; 68(8):2736-44. DOI: 10.1158/0008-5472.CAN-07-2290
Source: PubMed


Genistein (4',5,7-trihydroxyisoflavone) is the most abundant isoflavone found in the soybean. The effects of genistein on various cancer cell lines have been extensively studied but the precise molecular mechanisms are not known. We report here the epigenetic mechanism of the action of genistein on androgen-sensitive (LNCaP) and androgen-insensitive (DuPro) human prostate cancer cell lines. Genistein induced the expression of tumor suppressor genes p21 (WAF1/CIP1/KIP1) and p16 (INK4a) with a concomitant decrease in cyclins. There was a G(0)-G(1) cell cycle arrest in LNCaP cells and a G(2)-M arrest in DuPro cells after genistein treatment. Genistein also induced apoptosis in DuPro cells. DNA methylation analysis revealed the absence of p21 promoter methylation in both cell lines. The effect of genistein on chromatin remodeling has not been previously reported. We found that genistein increased acetylated histones 3, 4, and H3/K4 at the p21 and p16 transcription start sites. Furthermore, we found that genistein treatment also increased the expression of histone acetyl transferases that function in transcriptional activation. This is the first report on epigenetic regulation of various genes by genistein through chromatin remodeling in prostate cancer. Altogether, our data provide new insights into the epigenetic mechanism of the action of genistein that may contribute to the chemopreventive activity of this dietary isoflavone and have important implications for epigenetic therapy.

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    • "Epigenetic modalities of gene regulations have drawn considerable attention in the past few years and have been advanced for cancer prevention and therapy. Studies have shown that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors , either alone or in combinations, alter the expression status of TSGs in many human cancers (Brueckner et al., 2005; Fang et al., 2003; Majid et al., 2008). However, the use of synthetic inhibitors is generally associated with too many adverse side effects and many are not delivered well to solid tumors which limits the practical applications to chemoprevention and therapy. "
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    ABSTRACT: Available treatment strategies against estrogen receptor (ER)-negative breast cancer patients are limited due to their poor response to hormonal therapy. We have shown previously that the combinations of green tea polyphenols (GTPs), a dietary DNA methyltransferase inhibitor, and sulforaphane (SFN), a dietary histone deacetylase inhibitor, reactivate ERα expression in ERα-negative MDA-MB-231 cells. Here, we investigated the functional significance of ERα reactivation in the reactivation of silenced tumor suppressor genes (TSGs) in ERα-negative human breast cancer cells. We found that the treatment of MDA-MB-231 cells with the combinations of GTPs and SFN leads to the reactivation of silenced TSGs such as p21(CIP1/WAF1) and KLOTHO through active chromatin modifications. Further, GTPs- and SFN-mediated reactivation of TSGs was, at least in part, dependent on ERα reactivation in ERα-negative MDA-MB-231 cells. Collectively, our findings suggest that a novel combination of bioactive dietary supplements could further be explored as an effective therapeutic option against hormonal refractory breast cancer. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Feb 2015 · Molecular and Cellular Endocrinology
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    • "It acts synergistically with other drugs such as tamoxifen, cisplatin , 1,3-bis(2-chloroethyl)-1-nitrosourea, dexamethasone, daunorubicin, and tiazofurin. Genistein was also found to arrest cell cycle at G0-G1 phase in LNCaP cells and a G2/M phase in DuPro cells [144]. It activated the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification. "
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    ABSTRACT: This review describes the potential of a variety of physiologically active natural dietary polyphenols (PPhs) and their analogues, including derivatives of flavonoids, stilbenes, lignans, curcuminoids, and tannins, for prostate cancer chemotherapy. The large number of scientific papers on PPhs published during the last decade, particularly those focused on their therapeutic potential against prostate cancer cell lines, indicates rising interest in this group of compounds. Several polyphenolic agents are currently being investigated in advanced clinical trials as prominent cancer drug candidates while hundreds of related compounds are being evaluated in early clinical and preclinical studies. The review also covers the key mechanisms of antitumor action of natural PPhs against cancer cells.
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    • "Inhibition of proliferation, colony formation, and invasion; Apoptosis and cell cycle arrest Majid et al. 2010a; Kikuno et al. 2008; Chen et al. 2011; Majid et al. 2008, 2010b; Basak et al. 2008; Rabiau et al. 2011; Vardi et al. 2010 6. Green tea polyphenol (5–25 ␮mol/L) "
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    ABSTRACT: Prostate cancer is a disease that is greatly affected by lifestyle, particularly diet, and is more prevalent in US and European countries compared with South and East Asia. Among several known causes and risk factors, nutrition plays an important role in prostate cancer pathogenesis. Various dietary components including polyphenols have been shown to possess anticancer properties. Dietary polyphenols have been the subject of extensive studies for the last decade because of their anticancer and chemopreventive potentials. Besides possessing various antitumor properties, dietary polyphenols also contribute to epigenetic changes associated with the fate of cancer cells and have emerged as potential drugs for therapeutic intervention. Various polyphenols have been shown to affect DNA methylation, histone posttranslational modifications, and microRNA expression patterns in prostate cancer. In this review, we discuss the contribution of dietary polyphenols to various epigenetic modifications in prostate cancer. Since prostate cancer and diet are intimately associated, polyphenol-rich diets that epigenetically modify tumor biology have great significance in the prevention and management of prostate cancer.
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