Epigenetic alterations are involved in the overexpression of glutathione S-transferase π-1 in human colorectal cancers

Zhang,Rui; Kang,Kyoung  Ah; Piao,Mei Jing; Kim,Ki  Cheon; Zheng,Jian; Yao,Cheng  Wen; Cha,Ji  Won; Maeng,Young  Hee; Chang,Weon  Young; Moon,Pyong-Gon; Baek,Moon-Chang; Hyun,Jin  Won

doi:10.3892/ijo.2014.2522

Epigenetic alterations are involved in the overexpression of glutathione S-transferase π-1 in human colorectal cancers

Authors:
- Rui Zhang
- Kyoung Ah Kang
- Mei Jing Piao
- Ki Cheon Kim
- Jian Zheng
- Cheng Wen Yao
- Ji Won Cha
- Young Hee Maeng
- Weon Young Chang
- Pyong-Gon Moon
- Moon-Chang Baek
- Jin Won Hyun
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Affiliations: School of Medicine and Institute for Nuclear Science and Technology, Jeju National University, Jeju 690-756, Republic of Korea, Department of Molecular Medicine, Cell and Matrix Biology Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
Published online on: June 25, 2014 https://doi.org/10.3892/ijo.2014.2522
Pages: 1275-1283

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Abstract

Glutathione S-transferase π-1 (GSTP-1) is a member of the glutathione S-transferase enzyme superfamily, which catalyzes the conjugation of electrophiles to glutathione during the process of detoxification. In this study, the epigenetic alterations of GSTP-1 expression in human colorectal cancers and the underlying mechanisms were investigated. In 10 colon cancer patients, proteomic analysis revealed that expression of GSTP-1 protein was higher in tumor tissues than in paired adjacent normal tissues. Likewise, in 7 of 10 colon cancer patients, GSTP-1 protein expression was more than 1.5‑fold higher in tumor tissues than in adjacent normal tissues, as determined by western blotting. Immunohistochemical data confirmed that GSTP-1 protein was expressed at higher levels in colon cancer tissues compared to normal mucosa. GSTP-1 enzyme activity was closely correlated with GSTP-1 protein expression in colon cancer patients. Consistent with this, GSTP-1 mRNA, protein and activity levels were higher in the colorectal cancer cell lines Caco-2, HCT-116, HT-29, SNU-407 and SNU-1033 compared to the normal colon cell line FHC. Methylation-specific PCR results indicated that the high levels of GSTP-1 in human colorectal cancer cell lines were likely due to the lower degree of promoter methylation in colon cancer cell lines compared to the normal colon cell line, consistent with findings in colon cancer patients. Moreover, the levels of specific activator-protein complexes and histone marks were higher in human colorectal cancer cells compared to the normal human colon cell line, whereas the repressor protein complexes exhibited the opposite pattern. Furthermore, chromatin immunoprecipitation assays demonstrated that expression levels of the transcription factors AP-1 and SP-1 were correlated with the upregulation of GSTP-1 expression in colorectal cancer cells. Finally, knockdown of GSTP-1 promoted the sensitivity of SNU-407 cells to the anticancer agent 5-fluorouracil. These data indicate that GSTP-1 may serve as a clinically useful biomarker of colon cancer and a target for anti-colon cancer drugs.

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