Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells

Rui Zhang, Kyoung Ah Kang, Ki Cheon Kim, Soo Young Na, Weon Young Chang, Gi Young Kim, Hye Sun Kim, Jin Won Hyun

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The intestine-specific transcription factor, caudal type homeobox-1 (CDX1), is a candidate tumor suppressor gene that plays key roles in regulating intestinal epithelial differentiation and proliferation. It is aberrantly down-regulated in colorectal cancers and colon cancer-derived cell lines by promoter hypermethylation. Since the effects of oxidative stress on the transcription of tumor suppressor genes are largely unknown, this study explored the epigenetic alterations that occur during reactive oxygen species (ROS)-induced silencing of CDX1 in colorectal cancer cells. Oxidative stress by hydrogen peroxide (H2O2) down-regulated CDX1 mRNA levels and protein expression in the human colorectal cancer cell line, T-84. This down-regulation was abolished by pretreatment with the ROS scavenger, N-acetylcysteine. In addition, the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC) markedly attenuated the decrease in mRNA and protein expression levels induced by H2O2. Moreover, methylation-specific PCR data revealed that H2O2 treatment increased CDX1 promoter methylation, and treatment with 5-Aza-dC reversed this effect, suggesting that an epigenetic regulatory mechanism triggered by ROS-induced methylation may be involved in CDX1 expression. Furthermore, H2O2 treatment resulted in up-regulation of DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) expression and activity, and enhanced the association between DNMT1 and HDAC1. Taken together, these results suggest that ROS-induced oxidative stress silences the tumor suppressor CDX1 through epigenetic regulation, and may therefore be associated with the progression of colorectal cancer.

Original languageEnglish
Pages (from-to)214-219
Number of pages6
JournalGene
Volume524
Issue number2
DOIs
StatePublished - 25 Jul 2013

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decitabine
Epigenomics
Colorectal Neoplasms
Reactive Oxygen Species
Oxidative Stress
Histone Deacetylase 1
Methylation
Methyltransferases
Tumor Suppressor Genes
Colonic Neoplasms
Cell Line
Messenger RNA
Homeobox Genes
DNA
Acetylcysteine
DNA Methylation
Hydrogen Peroxide
Intestines
Proteins
Transcription Factors

Keywords

  • Caudal type homeobox-1
  • Colorectal cancer
  • Epigenetic alteration
  • Oxidative stress
  • Reactive oxygen species
  • Tumor suppressor gene

Cite this

Zhang, R., Kang, K. A., Kim, K. C., Na, S. Y., Chang, W. Y., Kim, G. Y., ... Hyun, J. W. (2013). Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells. Gene, 524(2), 214-219. https://doi.org/10.1016/j.gene.2013.04.024
Zhang, Rui ; Kang, Kyoung Ah ; Kim, Ki Cheon ; Na, Soo Young ; Chang, Weon Young ; Kim, Gi Young ; Kim, Hye Sun ; Hyun, Jin Won. / Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells. In: Gene. 2013 ; Vol. 524, No. 2. pp. 214-219.
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abstract = "The intestine-specific transcription factor, caudal type homeobox-1 (CDX1), is a candidate tumor suppressor gene that plays key roles in regulating intestinal epithelial differentiation and proliferation. It is aberrantly down-regulated in colorectal cancers and colon cancer-derived cell lines by promoter hypermethylation. Since the effects of oxidative stress on the transcription of tumor suppressor genes are largely unknown, this study explored the epigenetic alterations that occur during reactive oxygen species (ROS)-induced silencing of CDX1 in colorectal cancer cells. Oxidative stress by hydrogen peroxide (H2O2) down-regulated CDX1 mRNA levels and protein expression in the human colorectal cancer cell line, T-84. This down-regulation was abolished by pretreatment with the ROS scavenger, N-acetylcysteine. In addition, the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC) markedly attenuated the decrease in mRNA and protein expression levels induced by H2O2. Moreover, methylation-specific PCR data revealed that H2O2 treatment increased CDX1 promoter methylation, and treatment with 5-Aza-dC reversed this effect, suggesting that an epigenetic regulatory mechanism triggered by ROS-induced methylation may be involved in CDX1 expression. Furthermore, H2O2 treatment resulted in up-regulation of DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) expression and activity, and enhanced the association between DNMT1 and HDAC1. Taken together, these results suggest that ROS-induced oxidative stress silences the tumor suppressor CDX1 through epigenetic regulation, and may therefore be associated with the progression of colorectal cancer.",
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Zhang, R, Kang, KA, Kim, KC, Na, SY, Chang, WY, Kim, GY, Kim, HS & Hyun, JW 2013, 'Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells', Gene, vol. 524, no. 2, pp. 214-219. https://doi.org/10.1016/j.gene.2013.04.024

Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells. / Zhang, Rui; Kang, Kyoung Ah; Kim, Ki Cheon; Na, Soo Young; Chang, Weon Young; Kim, Gi Young; Kim, Hye Sun; Hyun, Jin Won.

In: Gene, Vol. 524, No. 2, 25.07.2013, p. 214-219.

Research output: Contribution to journalArticle

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T1 - Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells

AU - Zhang, Rui

AU - Kang, Kyoung Ah

AU - Kim, Ki Cheon

AU - Na, Soo Young

AU - Chang, Weon Young

AU - Kim, Gi Young

AU - Kim, Hye Sun

AU - Hyun, Jin Won

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N2 - The intestine-specific transcription factor, caudal type homeobox-1 (CDX1), is a candidate tumor suppressor gene that plays key roles in regulating intestinal epithelial differentiation and proliferation. It is aberrantly down-regulated in colorectal cancers and colon cancer-derived cell lines by promoter hypermethylation. Since the effects of oxidative stress on the transcription of tumor suppressor genes are largely unknown, this study explored the epigenetic alterations that occur during reactive oxygen species (ROS)-induced silencing of CDX1 in colorectal cancer cells. Oxidative stress by hydrogen peroxide (H2O2) down-regulated CDX1 mRNA levels and protein expression in the human colorectal cancer cell line, T-84. This down-regulation was abolished by pretreatment with the ROS scavenger, N-acetylcysteine. In addition, the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC) markedly attenuated the decrease in mRNA and protein expression levels induced by H2O2. Moreover, methylation-specific PCR data revealed that H2O2 treatment increased CDX1 promoter methylation, and treatment with 5-Aza-dC reversed this effect, suggesting that an epigenetic regulatory mechanism triggered by ROS-induced methylation may be involved in CDX1 expression. Furthermore, H2O2 treatment resulted in up-regulation of DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) expression and activity, and enhanced the association between DNMT1 and HDAC1. Taken together, these results suggest that ROS-induced oxidative stress silences the tumor suppressor CDX1 through epigenetic regulation, and may therefore be associated with the progression of colorectal cancer.

AB - The intestine-specific transcription factor, caudal type homeobox-1 (CDX1), is a candidate tumor suppressor gene that plays key roles in regulating intestinal epithelial differentiation and proliferation. It is aberrantly down-regulated in colorectal cancers and colon cancer-derived cell lines by promoter hypermethylation. Since the effects of oxidative stress on the transcription of tumor suppressor genes are largely unknown, this study explored the epigenetic alterations that occur during reactive oxygen species (ROS)-induced silencing of CDX1 in colorectal cancer cells. Oxidative stress by hydrogen peroxide (H2O2) down-regulated CDX1 mRNA levels and protein expression in the human colorectal cancer cell line, T-84. This down-regulation was abolished by pretreatment with the ROS scavenger, N-acetylcysteine. In addition, the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC) markedly attenuated the decrease in mRNA and protein expression levels induced by H2O2. Moreover, methylation-specific PCR data revealed that H2O2 treatment increased CDX1 promoter methylation, and treatment with 5-Aza-dC reversed this effect, suggesting that an epigenetic regulatory mechanism triggered by ROS-induced methylation may be involved in CDX1 expression. Furthermore, H2O2 treatment resulted in up-regulation of DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) expression and activity, and enhanced the association between DNMT1 and HDAC1. Taken together, these results suggest that ROS-induced oxidative stress silences the tumor suppressor CDX1 through epigenetic regulation, and may therefore be associated with the progression of colorectal cancer.

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