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      Call for Papers: Preclinical Investigations of Nutrigenetic/Nutrigenomic Targets

      Submit here before January 31, 2025

      About Lifestyle Genomics: 2.0 Impact Factor I 4.0 CiteScore I 0.539 Scimago Journal & Country Rank (SJR)

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      Epigenetic Control of Estrogen Receptor Expression and Tumor Suppressor Genes Is Modulated by Bioactive Food Compounds

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          Abstract

          Background: The tumor suppressor genes p15<sup>INK4b</sup> and p16<sup>INK4a</sup> as well as the estrogen receptor-α (ESR1) gene are abnormally methylated and expressed in colon cancer. The cancer-preventative abilities of several bioactive food components have been linked to their estrogenic and epigenetic activities. Methods: The effect of folic acid, zebularine, resveratrol, genistein and epigallocatechin-3-gallate (EGCG) on tumor cell growth, promoter methylation of ESR1, p15<sup>INK4b</sup> and p16<sup>INK4a</sup> and gene expression of ESR1 and ESR2 was analyzed in Caco-2 cells. Gene expression was measured using real-time PCR, and promoter CpG methylation was assessed using bisulfite conversion and methylation-specific PCR. Results: After exposure to a high concentration of folic acid (20 µmol/l), enhanced cancer cell growth and concomitant increased methylation of the ESR1 (3.6-fold), p16<sup>INK4a</sup> and p15<sup>INK4b</sup> promoters was observed. A lower concentration of folic acid (2 µmol/l) decreased cell growth. The phytoestrogens genistein and resveratrol enhanced expression of ESR1 (genistein 200 µmol/l: 2.1-fold; resveratrol 50 µmol/l: 6.3-fold) and ESR2 (2.6- and 3.6-fold, respectively). Genistein and resveratrol treatment increased promoter methylation of ESR1 (genistein 200 µmol/l: 2.9-fold; resveratrol 50 µmol/l: 1.4-fold). For p16<sup>INK4a</sup>, increased methylation was found after exposure to 10 µmol/l resveratrol, but for p15<sup>INK4b</sup>, decreased methylation was found. Both components showed growth-inhibitory activities. For EGCG, growth inhibition at 100 µmol/l and suppressed promoter methylation of tumor suppressor genes (p16<sup>INK4a</sup>: 0.9-fold; p15<sup>INK4b</sup>: 0.6-fold) was seen. Conclusions: Our results show that these food compounds regulate ESR and tumor suppressor gene expression by multiple mechanisms including epigenetic processes. An improved understanding of these epigenetic effects could therefore support specific dietary concepts of epigenetic cancer prevention and intervention.

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          The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics.

          Y Sambuy, I. De Angelis, G Ranaldi … (2005)
          The human intestinal Caco-2 cell line has been extensively used over the last twenty years as a model of the intestinal barrier. The parental cell line, originally obtained from a human colon adenocarcinoma, undergoes in culture a process of spontaneous differentiation that leads to the formation of a monolayer of cells, expressing several morphological and functional characteristics of the mature enterocyte. Culture-related conditions were shown to influence the expression of these characteristics, in part due to the intrinsic heterogeneity of the parental cell line, leading to selection of sub-populations of cells becoming prominent in the culture. In addition, several clonal cell lines have been isolated from the parental line, exhibiting in general a more homogeneous expression of differentiation traits, while not always expressing all characteristics of the parental line. Culture-related conditions, as well as the different Caco-2 cell lines utilized in different laboratories, often make it extremely difficult to compare results in the literature. This review is aimed at summarizing recent, or previously unreviewed, data from the literature on the effects of culture-related factors and the influence of line sub-types (parental vs. different clonal lines) on the expression of differentiation traits important for the use of Caco-2 cells as a model of the absorptive and defensive properties of the intestinal mucosa. Since the use of Caco-2 cells has grown exponentially in recent years, it is particularly important to highlight these methodological aspects in order to promote the standardization and optimisation of this intestinal model.
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            Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy.

            Ming Zhu Fang, Dapeng Chen, Yi Sun … (2005)
            We have previously shown the reactivation of some methylation-silenced genes in cancer cells by (-)-epigallocatechin-3-gallate, the major polyphenol from green tea. To determine whether other polyphenolic compounds have similar activities, we studied the effects of soy isoflavones on DNA methylation. Enzyme assay was used to determine the inhibitory effect of genistein on DNA methyltransferase activity in nuclear extracts and purified recombinant enzyme. Methylation-specific PCR and quantitative real-time PCR were employed to examine the DNA methylation and gene expression status of retinoic acid receptor beta (RARbeta), p16INK4a, and O6-methylguanine methyltransferase (MGMT) in KYSE 510 esophageal squamous cell carcinoma cells treated with genistein alone or in combination with trichostatin, sulforaphane, or 2'-deoxy-5-aza-cytidine (5-aza-dCyd). Genistein (2-20 micromol/L) reversed DNA hypermethylation and reactivated RARbeta, p16INK4a, and MGMT in KYSE 510 cells. Genistein also inhibited cell growth at these concentrations. Reversal of DNA hypermethylation and reactivation of RARbeta by genistein were also observed in KYSE 150 cells and prostate cancer LNCaP and PC3 cells. Genistein (20-50 micromol/L) dose-dependently inhibited DNA methyltransferase activity, showing substrate- and methyl donor-dependent inhibition. Biochanin A and daidzein were less effective in inhibiting DNA methyltransferase activity, in reactivating RARbeta, and in inhibiting cancer cell growth. In combination with trichostatin, sulforaphane, or 5-aza-dCyd, genistein enhanced reactivation of these genes and inhibition of cell growth. These results indicate that genistein and related soy isoflavones reactivate methylation-silenced genes, partially through a direct inhibition of DNA methyltransferase, which may contribute to the chemopreventive activity of dietary isoflavones.
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              Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation.

              Kyung-Chul Choi, Myung Jung, Yoo-Hyun Lee … (2009)
              Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-kappaB (NF-kappaB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 micromol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IkappaBalpha, and suppresses tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. We also showed that EGCG prevents TNFalpha-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-kappaB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-kappaB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-kappaB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 micromol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases.
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                Author and article information

                Journal
                Journal ID (publisher-id): ANM
                Journal ID (nlm-ta): Ann Nutr Metab
                Journal ID (doi): 10.1159/issn.0250-6807
                Title: Annals of Nutrition and Metabolism
                Publisher: S. Karger AG
                ISSN (Print): 0250-6807
                ISSN (Electronic): 1421-9697
                Publication date Subscription-year: 2010
                Publication date (Print): January 2011
                Publication date (Electronic): 18 November 2010
                Volume: 57
                Issue: 3-4
                Pages: 183-189
                Affiliations
                aDepartment of Nutritional Sciences, University of Vienna, and bDepartment of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
                Author notes
                *Univ.-Doz. Dr. Alexander G. Haslberger, Department of Nutritional Sciences, Althanstrasse 14, UZAII, 2D 541, AT–1090 Vienna (Austria), Tel. +43 6991 2211 212, E-Mail alexander.haslberger@unvie.ac.at
                Article
                Publisher ID: 321514 Other ID: Ann Nutr Metab 2010;57:183–189
                DOI: 10.1159/000321514
                PubMed ID: 21088384
                SO-VID: 0815c4a9-b03c-4f9f-a0c7-01d45a2eaaee
                Copyright © © 2010 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 10 December 2009
                Date accepted : 09 September 2010
                Page count
                Figures: 1, Tables: 1, References: 51, Pages: 7
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Nutrition & Dietetics,Health & Social care,Public health
                Keywords: Epigallocatechin-3-gallate,Estrogen receptor-α,Resveratrol,Genistein,Folic acid,Epigenetic mechanisms,Colon cancer,Estrogen receptor-β,p15,p16,DNA methylation
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics, Health & Social care, Public health
                Keywords: Epigallocatechin-3-gallate, Estrogen receptor-α, Resveratrol, Genistein, Folic acid, Epigenetic mechanisms, Colon cancer, Estrogen receptor-β, p15, p16, DNA methylation

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