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

Published Jul 31, 2008Gut

Increased DNA methylation controls antioxidant enzyme levels in Barrett's adenocarcinoma

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Page updated Mar 29, 2026

Abstract

Hypermethylation was observed in more than 62% of Barrett's adenocarcinoma samples for key glutathione-related genes.

Four genes (GPX3, GPX7, GSTM2, and GSTM3) exhibited significant promoter DNA hypermethylation in Barrett's adenocarcinoma samples compared to normal tissue.
More than half of the adenocarcinoma samples showed downregulation of GPX3, GPX7, GSTM2, GSTM3, and GSTM5 at the mRNA level.
A significant inverse relationship was found between DNA methylation and mRNA expression for GPX3, GPX7, GSTM2, and GSTM5.
Treatment of oesophageal cancer cell lines with specific agents reversed the methylation pattern, leading to re-expression of the affected genes.
Immunohistochemical analysis revealed weak to absent staining of GPX3, GPX7, and GSTM2 in tumors, contrasting with stronger staining in normal tissue.

AI simplified

BACKGROUND: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSION: Epigenetic inactivation of members of the glutathione pathway can be an important mechanism in Barrett's tumourigenesis.

Full Text

Full text is available at the source.

View full text ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief