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This article was downloaded by: [Case Western Reserve University] On: 01 December 2014, At: 15:35 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Epigenetics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kepi20 Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis Qian Li & Hong Chen Published online: 01 Jul 2011. To cite this article: Qian Li & Hong Chen (2011) Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis, Epigenetics, 6:7, 849-852, DOI: 10.4161/epi.6.7.16314 To link to this article: http://dx.doi.org/10.4161/epi.6.7.16314 PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions

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Page 1: Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis

This article was downloaded by: [Case Western Reserve University]On: 01 December 2014, At: 15:35Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK

EpigeneticsPublication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/kepi20

Epigenetic modifications of metastasis suppressorgenes in colon cancer metastasisQian Li & Hong ChenPublished online: 01 Jul 2011.

To cite this article: Qian Li & Hong Chen (2011) Epigenetic modifications of metastasis suppressor genes in colon cancermetastasis, Epigenetics, 6:7, 849-852, DOI: 10.4161/epi.6.7.16314

To link to this article: http://dx.doi.org/10.4161/epi.6.7.16314

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) containedin the publications on our platform. However, Taylor & Francis, our agents, and our licensors make norepresentations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of theContent. Any opinions and views expressed in this publication are the opinions and views of the authors, andare not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon andshould be independently verified with primary sources of information. Taylor and Francis shall not be liable forany losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoeveror howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use ofthe Content.

This article may be used for research, teaching, and private study purposes. Any substantial or systematicreproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

Page 2: Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis

©2011 Landes Bioscience.Do not distribute.

www.landesbioscience.com Epigenetics 849

Epigenetics 6:7, 849-852; July 2011; © 2011 Landes Bioscience

POINT-OF-VIEW POINT-OF-VIEW

Key words: colorectal cancer, metastasis suppressor, NDRG1, E-cadherin, nm23, cell adhesion

Submitted: 04/29/11

Accepted: 05/05/11

DOI: 10.4161/epi.6.7.16314

*Correspondence to: Hong Chen; Email: [email protected]

Colon and rectal cancer (colorectal -cancer, CRC) is the third most

common cancer worldwide. Deaths from CRC account for around 8% of all cancer deaths, making it the fourth most common cause of death from can-cer. The high mortality rate of colon cancer is mainly attributable to its metastasis. Efforts have been made to identify metastasis suppressor genes, which encode proteins responsible for inhibiting the metastasis but not sup-pressing the growth of primary tumors. Studies on metastasis suppressor genes demonstrated that epigenetic modifi-cations, such as DNA promoter meth-ylation and histone modification, play crucial roles in regulating the expres-sion of many metastasis suppressor genes, which indicates the association between aberrant epigenetic alterations and cancer metastasis. This review will focus on the recent findings regarding metastasis suppressors regulated by epi-genetic modifications, particularly DNA methylation and histone modification, in CRC metastasis. Also, we will dis-cuss recent progress on the suppression of CRC metastasis by genistein, a soy isoflavone, with a focus on epigenetic mechanisms.

Introduction

Cancer metastasis is secondary to can-cer development; however, the high mortality of CRC is mainly attribut-able to its metastasis. Metastasis is the process by which primary tumors invade into and start to proliferate in a distant new site. Simply, it involves the

Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis

Qian Li and Hong Chen*Department of Food Science and Human Nutrition; University of Illinois at Urbana-Champaign; Urbana, IL USA

migration of primary tumors through the tumor stroma, intravasation into the vasculature, followed by the last step of “colonization.”1 Despite the recent and continuous improvements in diagnosis and treatments, more than 50% of colon and rectal cancers metastasize to liver, lung and lymph nodes.2 Five-year sur-vival rate remains below 50% for patients with metastatic CRC.

Metastasis suppressors (MS), encoded by metastasis suppressor genes, are mol-ecules that inhibit the process of metas-tasis without preventing growth of the primary tumor. At this time, over 20 MS have been confirmed in vivo. Some MS only inhibit the metastatic progress of one type of cancer, while others suppress metastasis in a variety of cancers. The mechanisms of MS are diverse, ranging from the alteration of cell adhesion, to induction of apoptosis and regulation of transcription.3 Based on published studies and on our own findings, epigenetic alter-ations play critical roles in regulating the expression of metastasis suppressor genes, which further affects the development of CRC metastasis. In this review, we assemble evidence to support the notion that CRC metastasis is in part controlled by epigenetic mechanisms through their regulation of the expression of metastasis suppressor genes.

Genistein, an isoflavone found mainly in soy, has been proposed to inhibit cancer cell metastasis.4 The role of genistein as a mediator of epigenetic regulation is also widely accepted. Here we propose that epigenetic mechanisms may contribute to the function of genistein in the inhibition of CRC metastasis.

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E-cadherin in cell-cell and/or cell-matrix adhesion, the expression of E-cadherin is inversely correlated to the quantity of migrating colon cancer cell lines, suggest-ing E-cadherin also regulates colon cancer cell migration.14

nm23 and CRC metastasis. The nm23 gene family is currently known to contain eight members, but not all of them have metastasis suppression capacity. nm23-H1 encodes the subunit A of nucleoside diphosphate kinase and is considered a MS. nm23-H1 was the first to be proposed as a prognostic factor in human CRC by Martinez et al. when they observed that both protein and mRNA of nm23-H1 were overexpressed in early stages of CRC while the expression was lost in more advanced CRC stages.15 A clinical study reported a negative correlation between nm23-H1 expression and lymph node metastasis in CRC patients by immuno-histochemistry.16 Furthermore, nm23-H1 silencing promoted cellular scattering, motility and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metallopro-teinases (MMP).17 Increased nm23-H1 expression was accompanied by a reduc-tion in motility, with minimal effect on proliferation.

In addition to NDRG1, E-cadherin and nm23-H1, the decreased expression of other MS, such as tissue inhibitors of metalloproteinases (TIMP), Raf kinase inhibitory protein (RKIP) and gelsolin have also been shown to correlate with advanced stages of CRC,18-20 but due to the limited length of this review, the regu-latory mechanisms of other MS in CRC metastasis will not be further discussed.

Epigenetic Regulation Contributes to the Silencing of CRC Metastasis Suppressors

Epigenetic modifications of NDRG1 gene. NDRG1 expression is regulated by both DNA methylation and histone modifications.21 The promoter region of human NDRG1 gene contains mul-tiple CpG sites, suggesting that tran-scription of NDRG1 can be regulated by DNA methylation. The transcription of NDRG1 in SW620 can be induced by DNA methylation inhibitor 5-aza-C in a

found both in vitro and in vivo. Guan et al. reported that expression of NDRG1 induced colon cancer cell differentiation.5 Overexpression of NDRG1 in SW620 induced morphological changes that are similar to changes induced by the differen-tiation reagent, tributyrin. Overexpression of NDRG1 greatly reduced the cells’ inva-sive ability through Matrigel, which is a rich source of extracellular matrix pro-teins.5 Athymic mice, when injected with invasive human colon cancer cell line SW620 which was overexpressed with NDRG1, had only 23% of liver metastases compared to 75% in the control group.5 A clinical study also showed that lower NDRG1 mRNA expression was correlated with shorter 5-year survival in colon can-cer patients.10

To demonstrate the relationship between NDRG1 and metastatic capa-bility, our group introduced siRNA that is specific to NDRG1 in SW480. Knockdown of NDRG1 in SW480 shifted the phenotype of SW480 toward the more invasive colon cancer cell line SW620 by affecting its adhesion capacity, cell cycle pattern and proliferation rate, indicating that NDRG1 plays a role in regulating all these aspects of the colon cancer cell profile.9

E-cadherin and CRC metastasis. E-cadherin is another MS downregulated in CRC metastases. E-cadherin (encoded by CDH1 gene) is a member of Ca2+-dependent adhesion molecules and is critical for maintaining tissue structure by regulating intercellular contacts.11 It is generally accepted that strongly expressed E-cadherin is present in cancers with tight cell-cell adhesion and weak inva-siveness; however, reduced expression of E-cadherin is commonly observed in can-cers with weak cell-cell adhesion and higher invasiveness. For example, E-cadherin expression was inversely correlated with higher stage and lymph node metastases of CRC as examined by immunohistochem-istry or in situ hybridization.12 Truant et al. reported that E-cadherin mRNA lev-els in CRC patients were higher in liver metastases than in adjacent normal tissues and higher expression was associated with lower occurrence of extrahepatic metas-tases after resection of liver metastases.13 In addition to the well-known function of

Downregulation of Metastasis Suppressors is Correlated with the Advanced Stages

and/or Metastasis of Colon Cancer

Metastasis is a multistep process. Different MS influence CRC metastasis by affect-ing different steps, including growth of the primary tumor, cell adhesion and cell migration. MS play roles in every aspect of these processes and below are some high-lighted MS.

NDRG1 and CRC metastasis. NDRG1 (also known as cap43/rit42/RTP/Drg1/TDD5) was first validated as a MS for CRC by Guan et al. In this study, NDRG1 mRNA expression was downreg-ulated or even silenced in metastatic colon cancer cells (SW620, LoVo and Colo205) when compared to primary colon can-cer cells (SW480, DLD-1, HCT116 and CaCO

2). Decreased mRNA expression of

NDRG1 was also detected in metastatic lesions of colon cancer patients.

SW480 and SW620 are two colon cancer cell lines sharing the same genetic background but different invasive abili-ties.6 SW480 was derived from a Dukes’ stage B colon carcinoma in a 50-year-old male patient, while SW620 was estab-lished from one of the lymph node metas-tases in the same patient one year later.6 Although the two cell lines are isogenic, they are remarkably different in many cell properties, such as cell morphology, resis-tance to apoptosis induction, tumouri-genicity, adhesion, migration capacity and metastatic potential.7,8 To compare the metastatic potential of SW480 and SW620 in vivo, Hewitt et al.7 injected 5 x 106 of either cell line into spleens of mice and found that SW620 generated far more surface metastases in livers than SW480. Because of their isogenic back-ground but distinct phenotypes, SW480 and SW620 can be used as a unique model for studying epigenetic modifica-tions in the late stages of colon cancer progression. Using this model, our group reported that NDRG1 mRNA in SW620 was approximately 40 times lower than in SW480. Accordingly, NDRG1 protein in SW620 was also greatly downregulated.9

Correlation of downregulated NDRG1 expression and CRC metastasis was

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reduced lung metastases of murine colon cancer cells by 44%.29 These findings have been supported by early clinical trials, in which subjects administered genistein showed decreased markers of advanced metastatic disease.4 Genistein has been shown to inhibit cancer metastasis through its ability to regulate nearly every step of the metastatic cascade, including cell adhesion, migration, invasion and angiogenesis.4,31 The effect of genistein on the metastatic cascade involves many MS or related signaling pathways, such as E-cadherin, MMP and NFkappaB.4

Genistein mediates alterations of his-tone acetylation as well as DNA methyla-tion of various genes in cancer cell lines.32-35 One of our studies showed that the time-dependent induction of WNT5a by genis-tein in colon cancer cell line SW1116 was correlated with decreased methyla-tion of a CpG island within its promoter as determined by bisulfite sequencing.35 Demethylation of CpGs, inhibition of Dnmt and MBD2 activity, and activation of the histones by acetylation and demeth-ylation at the BTG3 promoter followed by genistein treatment were observed in renal cancer cells.32 In animal models, dietary genistein intake has been shown to alter epigenetic patterns in rats and mice.36,37 Using the mouse differential methylation hybridization array, alteration of DNA methylation in specific genes in mice was observed following feeding of a genistein containing diet compared to that in mice fed a control casein diet.37 Other direct evidence that genistein affected DNA methylation was that maternal exposure to dietary genistein altered the epigenome of offspring in viable yellow agouti (Avy/a) mice. Overall, the potential of genistein as an effective epigenome modifier, which may greatly impact CRC metastasis, high-lights the potential ability of dietary genis-tein to improve CRC prognosis.

Conclusion and Perspectives

MS is a group of molecules closely associ-ated with cancer metastasis. With increas-ing numbers of MS discovered, it is urgent to clarify the mechanisms of MS regula-tion and their functions. Although genet-ics plays an important role in controlling MS, it remains impractical to utilize gene

in six human cancer cell lines by bisulfite sequencing.24 CpG sites in the CDH1 pro-moter were completely methylated in cell lines expressing E-cadherin, i.e., Lu-135, HeLa and HL-60. However, CDH1 was almost completely unmethylated in H358, HT-29 and MKN74, which do not express E-cadherin.

Histone modifications also play an important role in regulating E-cadherin expression. In the study by Yang et al.25 E-cadherin loss during the epithelial-to-mesenchymal transition (EMT) of immortalized mouse mammary gland epi-thelial cells (NMuMG) induced by TGFβ coincided with a decrease in active histone modifications (H3K9Ac and H3K4me3) and an increase in the repressive histone modification H3K27me3. Furthermore, reversal of the EMT by TGFβ withdrawal restored E-cadherin expression as well as H3K9Ac and H3K4me3 modifications. However, DNA methylation inhibitor 5-aza did not facilitate the reverse of EMT.

Expression of nm23-H1 was also regu-lated by DNA methylation, although it has been less studied than NDRG1 and E-cadherin. Two CpG islands are pres-ent in the promoter of nm23-H1. Five-Aza-2'-deoxycytidine (5-Aza-CdR), a DNA methylation inhibitor, increased the nm23-H1 expression of metastati-cally competent human breast carcinoma cell lines. Moreover, 5-Aza-CdR-induced nm23-H1 expression in MDA-MB-231 cells was associated with demethylation of a specific CpG island. The combination of 5-Aza-CdR and TSA was not syner-gistic in inducing nm23-H1 expression.26 However, the epigenetic mechanism of nm23-H1 expression during CRC metas-tasis remains poorly understood.

Inhibition of Cancer Metastasis by an Epigenetic Regulator,

Genistein

Genistein, a soy isoflavone, has been shown to suppress metastasis in different cancer types, including prostate cancer,27 breast cancer28 and colon cancer.29 Genistein decreased bone and liver metastases in nude mice injected with green fluorescent protein (GFP)-tagged MDA-MB-435 cells,30 which is a highly metastatic human breast carcinoma cell line. Genistein also

dose-dependent manner, indicating that DNA methylation regulates NDRG1 expression.5,9 However, bisulfite sequenc-ing of a putative CpG island at the pro-moter region of the human NDRG1 gene revealed that there is minimal CpG meth-ylation in both SW480 and SW620 cell lines, suggesting that the region tested for DNA methylation (-770/-250) may not represent the regulatory region for DNA methylation of the gene.9

The expression of NDRG1 in SW620 was also upregulated by histone deacety-lase inhibitors trichostatin A, suberoyl-anilide hydroxamic acid and sodium butyrate.5,9 To further clarify the associa-tion of histone modification and down-regulation of NDRG1 in CRC metastasis, we compared the histone modifiers in SW480 and SW620 by chromatin immu-noprecipitation (ChIP) assay. Compared to SW620, much higher acetylated his-tone H4 in the promoter region, which usually contributes to gene upregulation, was detected in SW480. In addition to acetylated histone H4, di-methylated H3 lysine4 (Me2H3K4) was also decreased in the coding region of NDRG1 in SW620, suggesting that it may be involved in the loss of NDRG1 in CRC metastasis.9

Epigenetic modifications of other metastasis suppressor genes. Regulation of E-cadherin expression by epigenetic modifications has been reported by many groups. Hypermethylation has been shown to be a major contributor to the decreased E-cadherin expression. Garinis et al. examined the methylation status of the E-cadherin promoter by methylation-specific polymerase chain reaction (MSP) in sporadic colorectal carcinomas and they observed a significant inverse association between the E-cadherin methylated alleles and E-cadherin mRNA level.22 Darwanto et al. proposed that expression of methyl-CpG-binding protein (MeCP) 2, which acts as a transcriptional repressor by non-specifically binding to methyl-CpGs and promoter methylation cooperatively regulate the expression of E-cadherin in colon cancer.23 Interestingly, hemi-methylation of E-cadherin as well as het-erogeneous expression of MeCP2 were observed especially at the invasion site. Kao et al. tested the methylation of 33 CpG sites in the CDH1 promoter region

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25. Yang X, Pursell B, Lu S, Chang TK, Mercurio AM. Regulation of beta 4-integrin expression by epigen-etic modifications in the mammary gland and during the epithelial-to-mesenchymal transition. J Cell Sci 2009; 122:2473-80.

26. Hartsough MT, Clare SE, Mair M, Elkahloun AG, Sgroi D, Osborne CK, et al. Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition. Cancer Res 2001; 61:2320-7.

27. Banerjee S, Kong D, Azmi A, Wang Z, Ahmad A, Sethi S, et al. Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo. Int J Cancer 2011; 128:1240-50.

28. Shao ZM, Wu J, Shen ZZ, Barsky SH. Genistein inhibits both constitutive and EGF-stimulated inva-sion in ER-negative human breast carcinoma cell lines. Anticancer Res 1998; 18:1435-9.

29. Ogasawara M, Matsunaga T, Suzuki H. Differential effects of antioxidants on the in vitro invasion, growth and lung metastasis of murine colon cancer cells. Biol Pharm Bull 2007; 30:200-4.

30. Martínez-Montemayor M, Otero-Franqui E, Martinez J, De La Mota-Peynado A, Cubano L, Dharmawardhane S. Individual and combined soy isoflavones exert differential effects on metastat-ic cancer progression. Clin Exp Metastasis 2010; 27:465-80.

31. Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of survival, proliferation, invasion, angio-genesis and metastasis of tumor cells through modu-lation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 2010; 29:405-34.

32. Majid S, Dar AA, Ahmad AE, Hirata H, Kawakami K, Shahryari V, et al. BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis 2009; 30:662-70.

33. King-Batoon A, Leszczynska JM, Klein CB. Modulation of gene methylation by genistein or lycopene in breast cancer cells. Environ Mol Mutagen 2008; 49:36-45.

34. Fang MZ, Chen D, Sun Y, Jin Z, Christman JK, Yang CS. Reversal of hypermethylation and reactivation of p16INK4a, RARbeta and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 2005; 11:7033-41.

35. Wang Z, Chen H. Genistein increases gene expres-sion by demethylation of WNT5a promoter in colon cancer cell line SW1116. Anticancer Res 2010; 30:4537-45.

36. Xiao R, Badger T, Simmen F. Dietary exposure to soy or whey proteins alters colonic global gene expression profiles during rat colon tumorigenesis. Molecular Cancer 2005; 4:1.

37. Day JK, Bauer AM, DesBordes C, Zhuang Y, Kim BE, Newton LG, et al. Genistein alters methylation patterns in mice. J Nutr 2002; 132:2419-23.

10. Strzelczyk B, Szulc A, Rzepko R, Kitowska A, Skokowski J, Szutowicz A, et al. Identification of high-risk stage II colorectal tumors by combined analysis of the NDRG1 gene expression and the depth of tumor invasion. Ann Surg Oncol 2009; 16:1287-94.

11. Takeichi M. Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 1995; 7:619-27.

12. Dorudi S, Sheffield JP, Poulsom R, Northover JM, Hart IR. E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am J Pathol 1993; 142:981-6.

13. Truant SC, Gouyer VP, Leteurtre EA, Zerimech F, Huet GM, Pruvot FR. E-cadherin and beta-catenin mRNA levels throughout colon cancer progression. J Surg Res 2008; 150:212-8.

14. Masur K, Lang K, Niggemann B, Zanker KS, Entschladen F. High PKCalpha and low E-cadherin expression contribute to high migratory activity of colon carcinoma cells. Mol Biol Cell 2001; 12:1973-82.

15. Martinez JA, Prevot S, Nordlinger B, Nguyen TM, Lacarriere Y, Munier A, et al. Overexpression of nm23-H1 and nm23-H2 genes in colorectal carci-nomas and loss of nm23-H1 expression in advanced tumour stages. Gut 1995; 37:712-20.

16. Elagoz S, Egilmez R, Koyuncu A, Muslehiddinoglu A, Arici S. The intratumoral microvessel density and expression of bFGF and nm23-H1 in colorectal cancer. Pathol Oncol Res 2006; 12:21-7.

17. Boissan M, De WO, Lizarraga F, Wendum D, Poincloux R, Chignard N, et al. Implication of metastasis suppressor NM23-H1 in maintaining adherens junctions and limiting the invasive potential of human cancer cells. Cancer Res 2010; 70:7710-22.

18. Asano T, Tada M, Cheng S, Takemoto N, Kuramae T, Abe M, et al. Prognostic values of matrix metal-loproteinase family expression in human colorectal carcinoma. J Surg Res 2008; 146:32-42.

19. Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR, et al. Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer. Am J Clin Pathol 2007; 127:820-7.

20. Litwin M, Mazur AJ, Nowak D, Mannherz HG, Malicka-Blaszkiewicz M. Gelsolin in human colon adenocarcinoma cells with different metastatic poten-tial. Acta Biochim Pol 2009; 56:739-43.

21. Kovacevic Z, Richardson DR. The metastasis sup-pressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis 2006; 27:2355-66.

22. Garinis GA, Menounos PG, Spanakis NE, Papadopoulos K, Karavitis G, Parassi I, et al. Hypermethylation-associated transcriptional silenc-ing of E-cadherin in primary sporadic colorectal carcinomas. J Pathol 2002; 198:442-9.

23. Darwanto A, Kitazawa R, Maeda S, Kitazawa S. MeCP2 and promoter methylation cooperatively regulate E-cadherin gene expression in colorectal carcinoma. Cancer Sci 2003; 94:442-7.

24. Kao RH, Huang LC, Hsu YH. Mapping the methyla-tion pattern by bisulfite genomic sequencing of the E-cadherin promoter CpG island in nasopharyngeal carcinoma. Anticancer Res 2002; 22:4109-13.

therapy based on MS to prevent cancer metastasis clinically.1 Compared to gene therapy, epigenetic treatments, such as DNA demethylation inhibitors and his-tone modifiers are more practical and have been applied to the treatment of several cancers. Therefore, we have summarized the most-studied MS that are related to CRC metastasis and are potentially regu-lated by epigenetic mechanism. Dietary factors capable of suppressing CRC metas-tasis are also promising, since the inci-dence of CRC is highly related to diet. As an epigenetic modifier, dietary genistein could potentially assist in the treatment of CRC as well as its metastasis. Here, we emphasized the significant impact of epi-genetic regulations on CRC metastasis. We hope to encourage more studies related to the epigenetic mechanisms behind CRC metastasis and to further stimulate interest in the epigenetic approaches for clinical cancer treatment.

References1. Stafford LJ, Vaidya KS, Welch DR. Metastasis sup-

pressors genes in cancer. Int J Biochem Cell Biol 2008; 40:874-91.

2. Segal NH, Saltz LB. Evolving treatment of advanced colon cancer. Annu Rev Med 2009; 60:207-19.

3. Hurst DR, Welch DR. Metastasis suppressor genes at the interface between the environment and tumor cell growth. Int Rev Cell Mol Biol 2011; 286:107-80.

4. Pavese J, Farmer R, Bergan R. Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metastasis Rev 2010; 29:465-82.

5. Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a Differentiation-related, putative meta-static suppressor gene in human colon cancer. Cancer Research 2000; 60:749-55.

6. Leibovitz A, Stinson JC, McCombs WB, III, McCoy CE, Mazur KC, Mabry ND. Classification of human colorectal adenocarcinoma cell lines. Cancer Res 1976; 36:4562-9.

7. Hewitt RE, McMarlin A, Kleiner D, Wersto R, Martin P, Tsokos M, et al. Validation of a model of colon cancer progression. J Pathol 2000; 192:446-54.

8. Hewitt RE, Brown KE, Corcoran M, Stetler-Stevenson WG. Increased expression of tissue inhibi-tor of metalloproteinases type 1 (TIMP-1) in a more tumourigenic colon cancer cell line. J Pathol 2000; 192:455-9.

9. Li Q, Chen H. Transcriptional silencing of N-Myc downstream-regulated gene 1 (NDRG1) in metastat-ic colon cancer cell line SW620. Clin Exp Metastasis 2011; 28:127-35.

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