Cancer Prevention by Epigenetic Modulation of Phytochemicals
Keywords:Dietary agents, microRNA, DNA methylation, epigenetics, cancer chemoprevention
"Epigenetics," which emphasizes the impact of active dietary agents on the function of epigenetics, has become an exciting new field of study in recent years. Focusing on aberrant epigenetic alterations during earlier carcinogenesis has been considered in cancer chemotherapy research since, unlike genetic mutations, these differences are reversible. Genes that operate as signal transducers, nuclear receptors, cell cycle regulators, and transcription factors, among others, can be silenced by abnormal epigenetic processes such as DNA promoter methylation, histone changes, and post-transcriptional modifications mediated by miRNA. DNA, gene product maintenance, apoptosis-inducing, and ultimately result in carcinogenesis. An analysis of several natural phytochemicals has been performed on food and medicinal plants to recognize potential and develop anticancer agents that cause the minor lesion to normal cells and effectively destroy cancer cells. A study of several natural phytochemicals found in food and medicinal plants was conducted in order to identify potential and develop anticancer agents that cause a minor lesion in normal cells while effectively destroying cancer cells. According to this study, plant phytochemicals may be involved in the targeted epigenetic modulation of miRNAs, DNA methyltransferases, histone altering enzymes, and carcinogenesis.
Henikoff S, Matzke MA. Exploring and explaining epigeneticeffects. Trends Genet. 1997;13:293–5.
Dehan P, KustermansG, Guenin S,Horion J, Boniver J, DelvenneP. DNA methylation and cancer diagnosis: new methods and applications. Expert Rev Mol Diagn. 2009;9:651–7.
Illingworth R, Kerr A, Desousa D, Jorgensen H, Ellis P,Stalker J, et al. A novel CpG island set identifies tissuespecific methylation at developmental gene loci. PLoS Biol. 2008;6:e22.
Suter MA, Aagaard-Tillery KM. Environmental influences on epigenetic profiles. Semin Reprod Med. 2009;27:380–90.
Jones PA, Baylin SB. The epigenomics of cancer. Cell.2007;128:683–92.
Issa JP, Kantarjian HM. Targeting DNA methylation. ClinCancer Res. 2009;15:3938–46.
Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8:286–98.
Kopelovich L, Crowell JA, Fay JR. The epigenome as a target forcancer chemoprevention. J Natl Cancer Inst. 2003;95:1747–57.
Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R,Kuo KC, Gehrke CW, et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res.1983;11:6883–94.
Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985;228:187–90.
Fullgrabe J, Kavanagh E, Joseph B. Histone onco-modifications. Oncogene. 2011;30:3391–403.
Mottet D, Castronovo V. Histone deacetylases: target enzymesfor cancer therapy. Clin Exp Metastasis. 2008;25:183–9.
Sauve AA, Wolberger C, Schramm VL, Boeke JD. The biochemistry of sirtuins. Annu Rev Biochem. 2006;75:435–65.
Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.
Spange S, Wagner T, Heinzel T, Kramer OH. Acetylation ofnon-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2009;41:185–98.
Calin GA, Croce CM. MicroRNA signatures in human cancers.Nat Rev Cancer. 2006;6:857–66.
Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Manyroads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11:228–34.
Brait M, Sidransky D. Cancer epigenetics: above and beyond.Toxicol Mech Methods. 2011;21:275–88.
Hardy TM, Tollefsbol TO. Epigenetic diet: impact on theepigenome and cancer. Epigenomics. 2011;3:503–18.
Siddiqui IA, Adhami VM, Saleem M, Mukhtar H. Beneficial effects of tea and its polyphenols against prostate cancer. Mol Nutr Food Res. 2006;50:130–43.
Lee WJ, Shim JY, Zhu BT. Mechanisms for the inhibition ofDNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol. 2005;68:1018–30.
Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, et al. Tea polyphenol (-)-epigallocatechin-3- gallate inhibits DNA methyltransferase and reactivates methylation silenced genes in cancer cell lines. Cancer Res. 2003;63:7563–70.
Pandey M, Shukla S, Gupta S. Promoter demethylation andchromatin remodeling by green tea polyphenols leads to reexpression of GSTP1 in human prostate cancer cells. Int J Cancer. 2010;126:2520–33.
Nandakumar V, Vaid M, Katiyar SK. (-)-Epigallocatechin-3-gallatereactivates silenced tumor suppressorgenes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis. 2011;32:537–44.
Berletch JB, Liu C, Love WK, Andrews LG, Katiyar SK,Tollefsbol TO. Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG. J Cell Biochem.2008;103:509–19.
Meeran SM, Patel SN, Chan TH, Tollefsbol TO. A novelprodrug of epigallocatechin-3-gallate: differential epigenetic hTERT repression in human breast cancer cells. Cancer Prev Res (Phila). 2001;4:1243–54.
Volate SR, Muga SJ, Issa AY, Nitcheva D, Smith T, Wargovich MJ. Epigenetic modulation of the retinoid X receptor alpha by green tea in the azoxymethane-Apc Min/ + mouse model of intestinal cancer. Mol Carcinog. 2009;48:920–33.
Thakur VS, Gupta K, Gupta S. Green tea polyphenols causescell cycle arrest and apoptosis in prostate cancer cells by suppressing class I histone deacetylases. Carcinogenesis. 2012;33:377–84.
Thakur VS, Gupta K, Gupta S. Green tea polyphenols increasep53 transcriptional activity and acetylation by suppressing class I histone deacetylases. Int J Oncol. 2012;41:353–61.
Balasubramanian S, Adhikary G, Eckert RL. The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival. Carcinogenesis. 2010;31:496–503.
Tsang WP, Kwok TT. Epigallocatechin gallate up-regulation ofmiR-16 and induction of apoptosis in human cancer cells. J Nutr Biochem. 2010;21:140–6.
Fix LN, Shah M, Efferth T, Farwell MA, Zhang B. MicroRNAexpression profile of MCF-7 human breast cancer cells and the effect of green tea polyphenon-60. Cancer Genomics Proteomics. 2010;7:261–77.
Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibitsproliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199–225.
Liu Z, Xie Z, Jones W, Pavlovicz RE, Liu S, Yu J, et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 2009;19:706–9.
Khor TO, Huang Y, Wu TY, Shu L, Lee J, Kong AN. Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. Biochem Pharmacol. 2011;82:1073–8.
Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY et al. Epigenetic CpG demethylation of the promoter and reactivation of the expression of neurog1 by curcumin in prostate LNCaP cells. AAPS J. 2011:606–14.
Jha AK, Nikbakht M, Parashar G, Shrivastava A, Capalash N,Kaur J. Reversal of hypermethylation and reactivation of the RARbeta2 gene by natural compounds in cervical cancer cell lines. Folia Biol (Praha). 2010;56:195–200.
Marcu MG, Jung YJ, Lee S, Chung EJ, Lee MJ, Trepel J, et al. Curcumin is an inhibitor of p300 histone acetylatransferase. Med Chem. 2006;2:169–74.
Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, et al. Curcumin, a novel p300/CREBbinding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase dependent chromatin transcription. J Biol Chem. 2004;279:51163–71.
Kang J, Chen J, Shi Y, Jia J, Zhang Y. Curcumin-inducedhistone hypoacetylation: the role of reactive oxygen species. Biochem Pharmacol. 2005;69:1205–13.
Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G. Curcumin, bothhistone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch-1 in Raji cells. Basic Clin Pharmacol Toxicol. 2007;101:427–33.
Liu HL, Chen Y, Cui GH, Zhou JF. Curcumin, a potent antitumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation. Acta Pharmacol Sin. 2005;26(5):603–9.
Bora-Tatar G, Dayangac-Erden D, Demir AS, Dalkara S,Yelekci K, Erdem-Yurter H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: activity and docking studies. Bioorg Med Chem. 2009;17:5219–28.
Lee SJ, Krauthauser C, Maduskuie V, Fawcett PT, Olson JM,Rajasekaran SA. Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo. BMC Cancer. 2011;11:144. doi:10.1186/1471-2407-11-144.
Hua WF, Fu YS, Liao YJ, Xia WJ, Chen YC, Zeng YX, et al. Curcumin induces down- regulation of EZH2 expression through the MAPK pathway in MDA-MB-435 human breast cancer cells. Eur J Pharmacol. 2010;637:16–21.
Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R.Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther. 2008;7:464–73.
Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, SchaffertJM, et al. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res.2010;70:3606–17.
Zhang J, Zhang T, Ti X, Shi J, Wu C, Ren X, et al. Curcumin promotes apoptosis in A549/DDP multidrugresistant human lung adenocarcinoma cells through an miRNA signaling pathway. Biochem Biophys Res Commun. 2010;399:1–6.
Yang J, Cao Y, Sun J, Zhang Y. Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells. Med Oncol. 2010;27:1114–8.
Mudduluru G, George-William JN, Muppala S, Asangani IA,Regalla K, Nelson LD, et al. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep. 2011;31:185–97.
Clarke JD, Dashwood RH, Ho E. Multi-targeted prevention ofcancer by sulforaphane. Cancer Lett. 2008;269:291–304.
Traka M, Gasper AV, Smith JA, Hawkey CJ, Bao Y, MithenRF. Transcriptome analysis of human colon caco-2 cells exposed to sulforaphane. J Nutr. 2005;135:1865–72.
Meeran SM, Patel SN, Tollefsbol TO. Sulforaphane causesepigenetic repression of hTERT expression in human breast cancer cell lines. PLoS One. 2010;5(7):e11457.
Myzak MC, Karplus PA, Chung FL, Dashwood RH. A novelmechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res. 2004;64:5767–74.
Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E. Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis. 2006;27:811–9.
Pledgie-Tracy A, Sobolewski MD, Davidson NE. Sulforaphaneinduces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther. 2007;6:1013–21.
Myzak MC, Dashwood WM, Orner GA, Ho E, Dashwood RH.Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. FASEB J.2006;20:506–8.
Myzak MC, Tong P, Dashwood WM, Dashwood RH, Ho E.Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Exp Biol Med (Maywood). 2007;232:227–34.
Banerjee S, Kong D, Wang Z, Bao B, Hillman GG, Sarkar FH.Attenuation of multi-targeted proliferation-linked signaling by 3,30-diindolylmethane (DIM): from bench to clinic. Mutat Res. 2011;728:47–66.
Li Y, Li X, Guo B. Chemopreventive agent 3,30diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res. 2010;70:646–54.
Li Y, Vandenboom 2nd TG, Kong D, Wang Z, Ali S, Philip PA,et al. Up-regulation of miR- 200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69:6704–12.
Li Y, Vandenboom TG, Wang Z, Ali S, Philip PA, Sarkar FH.miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res. 2010;70:1486–95.
Jin Y, Zou X, Feng X. 3,30-Diindolylmethane negatively regulates Cdc25A and induces a G2/M arrest by modulation of microRNA 21 in human breast cancer cells. Anticancer Drugs. 2010;21:814–22.
Banerjee S, Li Y, Wang Z, Sarkar FH. Multi-targeted therapy ofcancer by genistein. Cancer Lett. 2008;269:226–42.
Fang MZ, Chen D, Sun Y, Jin Z. Reversal of hypermethylationand reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res. 2005;11(19 Pt 1):7033–41.
King-Batoon A, Leszczynska JM, Klein CB. Modulation ofgene methylation by genistein or lycopene in breast cancer cells. Environ Mol Mutagen. 2008;49:36–45.
Vardi A, Bosviel R, Rabiau N, Adjakly M, Satih S, DechelotteP, et al. Soy phytoestrogens modify DNA methylation of GSTP1, RASSF1A, EPH2 and BRCA1 promoter in prostate cancer cells. In Vivo. 2010;24:393–400.
Adjakly M, Bosviel R, Rabiau N, Boiteux JP, Bignon YJ, GuyL, et al. DNA methylation and soy phytoestrogens: quantitative study in DU-145 and PC-3 human prostate cancer cell lines. Epigenomics. 2011;3:795–803.
Wang Z, Chen H. Genistein increases gene expression bydemethylation of WNT5a promoter in colon cancer cell line SW1116. Anticancer Res. 2010;30:4537–45.
Majid S, Dar AA, Shahryari V, Hirata H, Ahmad A, Saini S, et al. Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell translocation gene 3 in prostate cancer. Cancer. 2010;116:66–76.
Qin W, Zhu W, Shi H, Hewett JE, Ruhlen RL, Macdonald RS,et al. Soy isoflavones have an antiestrogenic effect and alter mammary promoter hypermethylation in healthy premenopausal women. Nutr Cancer. 2009;61:238–44.
Majid S, Kikuno N, Nelles J, Noonan E, Tanaka Y, KawamotoK, et al. Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification. Cancer Res. 2008;68:2736–44.
Hong T, Nakagawa T, Pan W, Kim MY, Kraus WL, Ikehara T,et al. Isoflavones stimulate estrogen receptor-mediated core histone acetylation. Biochem Biophys Res Commun.2004;317:259–64.
Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H,Tanaka Y, et al. Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells. Int J Cancer. 2008;123:552–60.
Basak S, Pookot D, Noonan EJ, Dahiya R. Genistein downregulates androgen receptor by modulating HDAC6-Hsp90 chaperone function. Mol Cancer Ther. 2008;7:3195–202.
Parker LP, Taylor DD, Kesterson J, Metzinger DS, GercelTaylor C. Modulation of microRNA associated with ovarian cancer cells by genistein. Eur J Gynaecol Oncol. 2009;30:616–21.
Majid S, Dar AA, Saini S, Chen Y, Shahryari V, Liu J, et al. Regulation of minichromosome maintenance gene family by microRNA-1296 and genistein in prostate cancer. Cancer Res. 2010;70:2809–18.
Sun Q, Cong R, Yan H, Gu H, Zeng Y, Liu N, et al. Genistein inhibits growth of human uveal melanoma cells and affects microRNA-27a and target gene expression. Oncol Rep.2009;22:563–7.
Cheung KL, Kong AN. Molecular targets of dietary phenethylisothiocyanate and sulforaphane for cancer chemoprevention. AAPS J. 2010;12:87–97.
Wang LG, Beklemisheva A, Liu XM, Ferrari AC, Feng J,Chiao JW. Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer. Mol Carcinog. 2007;46:24–31.
Lea MA, Randolph VM, Lee JE, des Bordes C. Induction ofhistone acetylation in mouse erythroleukemia cells by some organosulfur compounds including allyl isothiocyanate. Int J Cancer. 2001;92:784–9.
Xiao L, Huang Y, Zhen R, Chiao JW, Liu D, Ma X. Deficient histone acetylation in acute leukemia and the correction by an isothiocyanate. Acta Haematol. 2010;123:71–6.
Huang YQ, Ma XD, Lai YD, Wang XZ, Chiao JW, Liu DL. Phenylhexyl isothiocyanate (PHI) regulates histone methylation and acetylation and induces apoptosis in SMMC-7721 cells. Zhonghua Gan Zang Bing Za Zhi.2010;18:209–12.
Izzotti A, Calin GA, Steele VE, Cartiglia C, Longobardi M,Croce CM, et al. Chemoprevention of cigarette smoke-induced alterations of microRNA expression in rat lungs. Cancer Prev Res (Phila). 2010;3:62–72.
Izzotti A, Larghero P, Cartiglia C, Longobardi M, Pfeffer U,Steele VE, et al. Modulation of microRNA expression by budesonide, phenethyl isothiocyanate and cigarette smoke in mouse liver and lung. Carcinogenesis. 2010;31:894–901.
Savouret JF, Quesne M. Resveratrol and cancer: a review.Biomed Pharmacother. 2002;56:84–7.
Stefanska B, Rudnicka K, Bednarek A, FabianowskaMajewska K. Hypomethylation and induction of retinoic acid receptor beta 2 by concurrent action of adenosine analogues and natural compounds in breast cancer cells. Eur J Pharmacol. 2010;638:47–53.
Tili E, Michaille JJ, Alder H, Volinia S, Delmas D, Latruffe N,et al. Resveratrol modulates the levels of microRNAs targeting genes encoding tumor-suppressors and effectors of TGF signaling pathway in SW480 cells. Biochem Pharmacol.2010;80:2057–65.
Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and surviving during BRCA1-associated tumorigenesis. Mol Cell. 2008;32:11–20.
Papoutsis AJ, Lamore SD, Wondrak GT, Selmin OI,Romagnolo DF. Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells. J Nutr. 2010;140:1607–14.
Ariga T, Seki T. Antithrombotic and anticancer effects of garlicderived sulfur compounds: a review. Biofactors. 2006;26:93–103.
Lea MA, Randolph VM, Patel M. Increased acetylation ofhistones induced by diallyl disulfide and structurally related molecules. Int J Oncol. 1999;15:347–52.
Druesne N, Pagniez A, Mayeur C, Thomas M, Cherbuy C,Duee PH, et al. Diallyl disulfide (DADS) increases histone acetylation and p21(waf1/cip1) expression in human colon tumor cell lines. Carcinogenesis. 2004;25:1227–36.
Giovannucci E. Tomatoes, tomato-based products, lycopene,and cancer: review of the epidemiologic literature. J Natl Cancer Inst. 1999;91:317–31.
Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, Roat E,et al. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med. 2011;2011:591356.
Tan S, Wang C, Lu C, Zhao B, Cui Y, Shi X, et al. Quercetin is able to demethylate the p16INK4a gene promoter. Chemotherapy. 2009;55:6–10.
Ruiz PA, Braune A, Holzlwimmer G, Quintanilla-Fend L,Haller D. Quercetin inhibits TNF- induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr. 2007;137:1208–15.
Lee WJ, Chen YR, Tseng TH. Quercetin induces FasL-relatedapoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol Rep. 2011;25:583–91.
Priyadarsini RV, Vinothini G, Murugan RS, Manikandan P,Nagini S, et al. The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. Nutr Cancer. 2011;63:218–26.
Heber D. Multi-targeted therapy of cancer by ellagitannins.Cancer Lett. 2008;269:262–8.
Wen XY, Wu SY, Li ZQ, Liu ZQ, Zhang JJ, Wang GF, et al.Ellagitannin (BJA3121), an anti-proliferative natural polyphenol compound, can regulate the expression of miRNAs in HepG2 cancer cells. Phytother Res. 2009;23:778–84.
How to Cite
Copyright (c) 2022 Hero I. Mohammed, Sahar Hassannejad, Hoshyar S. Ali
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
All PHAHS Journal articles are published under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0) which allows authors retain copyright and others may not use the material for commercial purposes. A commercial use is one primarily intended for commercial advantage or monetary compensation. If others remix, transform, or build upon the material, they may not distribute the modified material.
Copyright on any research article published by the PHAHS Open Access journal is retained by the author(s). Authors also grant any third party the right to use the article freely as long as its original authors, citation details and publisher are identified.
Use of the article in whole or part in any medium requires attribution suitable in form and content as follows: [Title of Article/Author/Journal Title and Volume/Issue. Copyright (c) [year] [copyright owner as specified in the Journal]. Links to the final article on PHAHS website are encouraged where applicable.
The CC BY-NC-ND 4.0 Creative Commons Attribution License does not affect the moral rights of authors, including without limitation the right not to have their work subjected to derogatory treatment. It also does not affect any other rights held by authors or third parties in the article, including trademark or patent rights, or the rights of privacy and publicity. Use of the article must not assert or imply, whether implicitly or explicitly, any connection with, endorsement or sponsorship of such use by the author, publisher or any other party associated with the article.