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Tumor Biology
Published in: Tumor Biology 2/2012

01-04-2012 | Research Article

Epigenetic changes induced by oxidative stress in colorectal cancer cells: methylation of tumor suppressor RUNX3

Authors: Kyoung Ah Kang, Rui Zhang, Gi Young Kim, Suk Chul Bae, Jin Won Hyun

Published in: Tumor Biology | Issue 2/2012

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Abstract

Runt domain transcription factor 3 (RUNX3) is a tumor suppressor that is silenced in cancer via hypermethylation of its promoter. This study investigated the mechanisms involved in reactive oxygen species (ROS)-induced silencing of RUNX3 in terms of epigenetic alteration since the effects of oxidative stress in tumor suppressor gene transcription are largely unknown. RUNX3 mRNA and protein expressions were down-regulated in response to hydrogen peroxide (H2O2) in the human colorectal cancer cell line SNU-407. This down-regulation was abolished with pretreatment of the ROS scavenger, N-acetylcysteine (NAC). Moreover, methylation-specific PCR data revealed that H2O2 treatment increased RUNX3 promoter methylation; however, NAC and the cytosine methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC), decreased it, suggesting that an epigenetic regulatory mechanism by ROS-induced methylation may be involved in RUNX3 silencing. H2O2 treatment resulted in DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) up-regulation with increased expression and activity, increased binding of DNMT1 to HADC1, and increased DNMT1 binding to the RUNX3 promoter. In addition, 5-Aza-dC treatment prevented the decrease in RUNX3 mRNA and protein levels by H2O2 treatment. Additionally, H2O2 treatment inhibited the nuclear localization and expression of RUNX3, which was abolished by NAC treatment. Furthermore, the down-regulation of RUNX3 expression by H2O2 also influenced cell proliferation. Taken together, the data suggested that ROS silenced the tumor suppressor, RUNX3, by epigenetic regulation and may therefore be associated with the progression of colorectal cancer.
Literature
1.
2.
Filomeno G, Rotilio G, Ciriolo MR. Disulfide relays and phosphorylative cascades: partners in redox-mediated signaling pathways. Cell Death Differ. 2005;12:1555–63.CrossRef
3.
Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada J, et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 2003;22:6335–45.PubMedCrossRef
4.
5.
6.
Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21:5427–40.PubMedCrossRef
7.
Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.PubMedCrossRef
8.
Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. 2004;266:37–56.PubMedCrossRef
9.
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160:1–40.PubMedCrossRef
10.
Lim SO, Gu JM, Kim MS, Kim HS, Park YN, Park CK, et al. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology. 2008;135:2128–40.PubMedCrossRef
11.
12.
Hiramatsu T, Osaki M, Ito Y, Tanji Y, Tokuyasu N, Ito H. Expression of RUNX3 protein in human esophageal mucosa and squamous cell carcinoma. Pathobiology. 2005;72:316–24.PubMedCrossRef
13.
Oshimo Y, Oue N, Mitani Y, Nakayama H, Kitadai Y, Yoshida K, et al. Frequent loss of RUNX3 expression by promoter hypermethylation in gastric carcinoma. Pathobiology. 2004;71:137–43.PubMedCrossRef
14.
Subramaniam MM, Chan JY, Yeoh GK, Quek T, Ito K, Salto-Tellez M. Molecular pathology of RUNX3 in human carcinogenesis. Biochim Biophys Acta. 2009;1796:315–31.PubMed
15.
Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002;109:113–24.PubMedCrossRef
16.
Inoue K, Ozaki S, Shiga T, Ito K, Masuda T, Okado N, et al. Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nat Neurosci. 2002;5:946–54.PubMedCrossRef
17.
Levanon D, Bettoun D, Harris-Cerruti C, Woolf E, Negreanu V, Eilam R, et al. The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J. 2002;21:3454–63.PubMedCrossRef
18.
Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T, et al. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell. 2002;111:621–33.PubMedCrossRef
19.
Kim TY, Lee HJ, Hwang KS, Lee M, Kim JW, Bang YJ, et al. Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest. 2004;84:479–84.PubMedCrossRef
20.
Nakase Y, Sakakura C, Miyagawa K, Kin S, Fukuda K, Yanagisawa A, et al. Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography. Br J Cancer. 2005;92:562–9.PubMed
21.
Ito K, Liu Q, Salto-Tellez M, Yano T, Tada K, Ida H, et al. RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res. 2005;65:7743–50.PubMedCrossRef
22.
Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M, et al. RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res. 2006;66:6512–20.PubMedCrossRef
23.
Subramaniam MM, Chan JY, Soong R, Ito K, Ito Y, Yeoh KG, et al. RUNX3 inactivation by frequent promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression. Breast Cancer Res Treat. 2009;113:113–21.PubMedCrossRef
24.
Subramaniam MM, Chan JY, Soong R, Ito K, Yeoh KG, Wong R, et al. RUNX3 inactivation in colorectal polyps arising through different pathways of colonic carcinogenesis. Am J Gastroenterol. 2009;104:426–36.PubMedCrossRef
25.
Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS, et al. RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell. 2008;14:226–37.PubMedCrossRef
26.
Blau S, Rubistein A, Bass P, Singaram C, Kohen R. Differences in the reducing power along the rat GI tract: lower antioxidant capacity of the colon. Mol Cell Biochem. 1999;194:185–91.PubMedCrossRef
27.
Hendricks CW, Kelly RW, Radley S, Donovan IA, Keighley MR, Neoptolemis JP. Lipid peroxidation and prostaglandins in colorectal cancer. British J of Surg. 1994;81:1219–23.CrossRef
28.
Van Driel BE, Lyon H, Hoogenraad DC, Anten S, Hansen U, Van Noorden CJ. Expression of CuZn- and Mn-superoxide dismutase in human colorectal neoplasms. Free Radic Biol Med. 1997;23:435–44.PubMedCrossRef
29.
Benhar M, Engelberg D, Levitzki A. ROS, stress-activated kinases and stress-signaling in cancer. EMBO Reports. 2002;3:420–5.PubMedCrossRef
30.
Skrzydlewska E, Sulkowski S, Koda M, Zalewski B, Kanczuga-Koda L, Sulkowska M. Lipid peroxidation and antioxidant status in colorectal cancer. World J Gastroenterol. 2005;11:403–6.PubMed
31.
Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways. Cell Signal. 2006;18:32–9.PubMedCrossRef
32.
Ku JL, Kang SB, Shin YK, Kang HC, Hong SH, Kim IJ, et al. Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene. 2004;23:6736–42.PubMedCrossRef
33.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.PubMedCrossRef
34.
Lee SH, Kim J, Kim WH, Lee YM. Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene. 2009;28:184–94.PubMedCrossRef
35.
Kondo Y, Shen L, Issa JP. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol. 2003;23:206–15.PubMedCrossRef
36.
Soong R, Shah N, Peh BK, Chong PY, Ng SS, Zeps N, et al. The expression of RUNX3 in colorectal cancer is associated with disease stage and patient outcome. Br J Cancer. 2009;100:676–9.PubMedCrossRef
37.
38.
Arsova-Sarafinovska Z, Eken A, Matevska N, Erdem O, Sayal A, Savaser A, et al. Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer. Clin Biochem. 2009;42:1228–35.PubMedCrossRef
39.
Lawless MW, O'Byrne KJ, Gray SG. Oxidative stress induced lung cancer and COPD: opportunities for epigenetic therapy. J Cell Mol Med. 2009;13:2800–21.PubMedCrossRef
40.
Fahrner JA, Eguchi S, Herman JG, Baylin SB. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res. 2002;62:7213–8.PubMed
41.
Li QL, Kim HR, Kim WJ, Choi JK, Lee YH, Kim HM, et al. Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer. Biochem Biophys Res Commun. 2004;314:223–8.PubMedCrossRef
42.
Melki JR, Vincent PC, Brown RD, Clark SJ. Hypermethylation of E-cadherin in leukemia. Blood. 2000;95:3208–13.PubMed
43.
Trojan J, Brieger A, Raedle J, Esteller M, Zeuzem S. 5′-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut. 2000;47:272–6.PubMedCrossRef
44.
Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I, Godwin AK. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet. 2001;10:3001–7.PubMedCrossRef
45.
Song SH, Jong HS, Choi HH, Inoue H, Tanabe T, Kim NK, et al. Transcriptional silencing of cyclooxygenase-2 by hyper-methylation of the 5′ CpG island in human gastric carcinoma cells. Cancer Res. 2001;61:4628–35.PubMed
46.
Zöchbauer-Müller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, et al. 5′ CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. Cancer Res. 2001;61:3581–5.PubMed
47.
Ku JL, Yoon KA, Kim IJ, Kim WH, Jang JY, Suh KS, et al. Establishment and characterisation of six human biliary tract cancer cell lines. Br J Cancer. 2002;87:187–93.PubMedCrossRef
48.
Suh ER, Ha CS, Rankin EB, Toyota M, Traber PG. DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines. J Biol Chem. 2002;277:35759–800.CrossRef
49.
van Engeland M, Roemen GM, Brink M, Pachen MM, Weijenberg MP, de Bruïne AP, et al. K-ras mutations and RASSF1A promoter methylation in colorectal cancer. Oncogene. 2002;21:3792–5.PubMedCrossRef
50.
Yang Q, Nakamura M, Nakamura Y, Yoshimura G, Suzuma T, Umemura T, et al. Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer. Clin Cancer Res. 2002;8:2890–3.PubMed
51.
Di Vinci A, Infusini E, Nigro S, Monaco R, Giaretti W. Intratumor distribution of 1p deletions in human colorectal adenocarcinoma is commonly homogeneous: indirect evidence of early involvement in colorectal tumorigenesis. Cancer. 1998;83:415–22.PubMedCrossRef
52.
Di Vinci A, Infusini E, Peveri C, Sciutto A, Geido E, Risio M, et al. Correlation between 1p deletions and aneusomy in human colorectal adenomas. Int J Cancer. 1998;75:45–50.PubMedCrossRef
53.
Tanaka K, Yanoshita R, Konishi M, Oshimura M, Maeda Y, Mori T, et al. Suppression of tumourigenicity in human colon carcinoma cells by introduction of normal chromosome 1p36 region. Oncogene. 1993;8:2253–8.PubMed
54.
Praml C, Finke LH, Herfarth C, Schlag P, Schwab M, Amler L. Deletion mapping defines different regions in 1p34.2-pter that may harbor genetic information related to human colorectal cancer. Oncogene. 1995;11:1357–62.PubMed
55.
Ogunbiyi OA, Goodfellow PJ, Gagliardi G, Swanson PE, Birnbaum EH, Fleshman JW, et al. Prognostic value of chromosome 1p allelic loss in colon cancer. Gastroenterology. 1997;113:761–6.PubMedCrossRef
56.
Baylin SB, Ohm JE. Epigenetic gene silencing in cancer? A mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 2006;6:107–16.PubMedCrossRef
57.
Pradhan S, Bacolla A, Wells RD, Roberts RJ. Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem. 1999;274:33002–10.PubMedCrossRef
58.
Bestor TH, The DNA. methyltransferases of mammals. Hum Mol Genet. 2000;92:395–402.
59.
Rountree MR, Bachman KE, Herman JG, Baylin SB. DNA methylation, chromatin inheritance, and cancer. Oncogene. 2001;20:3156–65.
60.
Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 2000;24:88–91.PubMedCrossRef
61.
Fuks F. DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev. 2005;15:490–538.PubMedCrossRef
Metadata
Title
Epigenetic changes induced by oxidative stress in colorectal cancer cells: methylation of tumor suppressor RUNX3
Authors
Kyoung Ah Kang
Rui Zhang
Gi Young Kim
Suk Chul Bae
Jin Won Hyun
Publication date
01-04-2012
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 2/2012
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-012-0322-6

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