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PMID: 18664505 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett's adenocarcinoma.

Gut ·Vol. 58 ·No. 1 ·2009-01-00 ·Pages 5-15

Peng DF, Razvi M, Chen H, Washington K, Roessner A, Schneider-Stock R, El-Rifai W

Abstract

The accumulation of reactive oxygen species and subsequent oxidative DNA damage underlie the development of Barrett's oesophagus (BO) and its progression to Barrett's dysplasia (BD) and adenocarcinoma (BAC). The promoter regions of 23 genes of the glutathione S-transferase (GST) and glutathione peroxidase (GPX) families were systematically analysed. Quantitative bisulfite pyrosequencing, real-time RT-PCR, western blot and immunohistochemical (IHC) analysis methods were utilised in this study. 14 genes were identified that have CpG islands around their transcription start sites: GSTs (GSTM2-M5, GSTA4, GSTP1, GSTZ1, GSTT2, GSTO1 and GSTO2) and GPXs (GPX1, GPX3, GPX4 and GPX7). Analysis of an initial set of 20 primary samples demonstrated promoter DNA hypermethylation and mRNA downregulation of GPX3, GPX7, GSTM2, GSTM3 and GSTM5 in more than half of the BAC samples. Further analysis of 159 primary human samples (37 normal, 11 BO, 11 BD and 100 BACs) indicated frequent hypermethylation (>or=10% methylation) of GPX3 (62%), GPX7 (67%), GSTM2 (69.1%) and GSTM3 (15%) in BACs. A significant inverse correlation between DNA methylation and mRNA expression level was shown for GPX3 (p<0.001), GPX7 (p = 0.002), GSTM2 (p<0.001) and GSTM5 (p = 0.01). Treatment of oesophageal cancer cell lines with 5-aza-2'-deoxycytidine and trichostatin-A led to reversal of the methylation pattern and re-expression of these genes at the mRNA and protein levels. The IHC analysis of GPX3, GPX7 and GSTM2 on a tissue microarray that contained 75 BACs with normal squamous oesophageal samples demonstrated an absent to weak staining in tumours (52% for GPX3, 57% for GPX7 and 45% for GSTM2) and a moderate to strong immunostaining in normal samples. Epigenetic inactivation of members of the glutathione pathway can be an important mechanism in Barrett's tumourigenesis.

MeSH Terms
Adenocarcinoma/enzymology,genetics,pathology Adult Aged Aged, 80 and over Antimetabolites, Antineoplastic/pharmacology Azacitidine/analogs & derivatives,pharmacology Barrett Esophagus/enzymology,genetics,pathology Cell Transformation, Neoplastic/genetics CpG Islands/genetics DNA Methylation DNA, Neoplasm/genetics Decitabine Disease Progression Down-Regulation Epigenesis, Genetic Esophageal Neoplasms/enzymology,genetics,pathology Gene Expression Regulation, Enzymologic/drug effects Glutathione Peroxidase/genetics Glutathione Transferase/genetics Humans Hydroxamic Acids/pharmacology Middle Aged Promoter Regions, Genetic/genetics RNA, Messenger/genetics RNA, Neoplasm/genetics Reverse Transcriptase Polymerase Chain Reaction/methods Tumor Cells, Cultured
Chemicals
Antimetabolites, Antineoplastic DNA, Neoplasm Hydroxamic Acids RNA, Messenger RNA, Neoplasm trichostatin A Decitabine Glutathione Peroxidase Glutathione Transferase Azacitidine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Peng D F
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Razvi M
Chen H
Washington K
Roessner A
Schneider-Stock R
El-Rifai W
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Article Info
Journal
Gut
Abbr.
Gut
ISSN
1468-3288
DOI
10.1136/gut.2007.146290
Published
2009-01-00
Epub
2008-00-29
Pages
5-15
Language
English
Region
England
NLM ID
2985108R
PMCID
PMC2845391
Subset
IM
Grants
NCI NIH HHS · R01 CA106176 · United States
NCI NIH HHS · R01 CA106176-06 · United States
NCI NIH HHS · R01 CA106176-07A1 · United States
Corrections
CommentIn
PMID: 19091824
External Links
PubMed source DOI: 10.1136/gut.2007.146290 PMC Full Text View journal details
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