Silencing of glutathione S-transferase P1 by promoter hypermethylation and its relationship to environmental chemical carcinogens in hepatocellular carcinoma.
Glutathione S-transferases (GSTs) are a family of isoenzymes that play an important role in protecting cells from cytotoxic and carcinogenic agents. GSTpi is encoded by the GSTP1 gene. GSTP1 null mice show an increased risk of skin tumorigenesis induced by carcinogens. GSTP1 is transcriptionally silenced by promoter hypermethylation in several human cancers including hepatocellular carcinoma (HCC). Methylation-specific PCR (MSP) was used to analyze the GSTP1 promoter hypermethylation status of 83 hepatocellular carcinoma tissues from Taiwan. Hypermethylation was detected in 38 of 83 (46%) tumors. GSTP1 expression by immunohistochemical staining of HCC tissue samples was significantly associated with methylation status. The relationship between methylation status and clinical parameters and tumor markers including environmental exposure to aflatoxin B1(AFB1) and polycyclic aromatic hydrocarbons (PAH), measured as DNA adducts, was also investigated. A statistically significant association was found between GSTP1 promoter hypermethylation and the level of AFB1-DNA adducts in tumor tissue (OR 2.81, 95% CI 1.03-7.70); a marginally significant association was found for adjacent non-tumor tissue (OR 2.57, 95% CI 0.97-6.80). There was no association between GSTP1 hypermethylation and PAH-DNA adducts in tumor or adjacent non-tumor tissues. These results suggest that epigenetic inactivation of GSTP1 plays an important role in the development of HCC and exposure to environmental carcinogens may be related to altered methylation of genes involved in hepatocarcinogenesis. The mechanism by which environmental exposures induce epigenetic changes in HCC needs further analysis.
Zhang
Yu-jing
YJ
Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, 701 West 168th Street, New York, NY 10032, USA.
Chen
Yu
Y
Ahsan
Habibul
H
Lunn
Ruth M
RM
Chen
Shu-Yuan
SY
Lee
Po-huang
PH
Chen
Chien-Jen
CJ
Santella
Regina M
RM
D016604:Aflatoxin B1 / Q000009:adverse effects; D002274:Carcinogens, Environmental / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018736:DNA Adducts; D019175:DNA Methylation; D004273:DNA, Neoplasm; D004781:Environmental Exposure; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013624:Taiwan
D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004273:DNA, Neoplasm; D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; C095911:polycyclic aromatic hydrocarbons-DNA adduct; D016604:Aflatoxin B1; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase