Detailed methylation analysis of the glutathione S-transferase π (GSTP1) gene in prostate cancer

Millar, Douglas; Ow, Kim; Paul, Cheryl L.; Russell, Pamela J.; Molloy, Peter L.; Clark, Susan J.

doi:10.1038/sj.onc.1202415

Cited by 208 publications

(141 citation statements)

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“…The GSTP1 variant genotype was seen in increased numbers of tumors of the kidney, bladder, pancreas and lung (To-Figueras et al, 1999;Simic et al, 2009;Vrana et al, 2009). GSTP1 has a polymorphic site at codon 105 (exon 5), where an A to G transition causes an Ile to Val substitution (Ile105Val), resulting in lower enzyme activity to variety of electrophilic molecules (Millar et al, 1999;Hayes et al, 2005;McIlwain et al, 2006). Numerous reports assessed the risk of colorectal cancer development in subjects carrying the variant Val GSTP1 allele; however, the results are controversial (Harries et al, 1997;Welfare et al, 1999;Kiyohara, 2000;Grubben et al, 2001;Loktionov et al, 2001;Seow et al, 2002;Ates et al, 2005;Sun et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The GSTP1 Ile105Val Polymorphism is not Associated with Susceptibility to Colorectal Cancer

Khabaz

2012

Asian Pacific Journal of Cancer Prevention

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The glutathione S transferase (GST) family is a major part of cellular defense mechanisms against endogenous and exogenous substances, many of which have carcinogenic potential. Alteration in the expression level or structure of the glutathione-S-transferase (GST) enzymes may lead to inadequate detoxification of potential carcinogens and consequently contribute to cancer development. A member of the glutathione-S-transferase (GST) family, GSTP1, is an attractive candidate for involvement in susceptibility to carcinogen-associated colorectal cancer. An AgG transition in exon 5 resulting in an Ile105Val amino acid substitution has been identified which alters catalytic efficiency. The present study investigated the possible impact of Ile105Val GSTP1 polymorphism on susceptibility to colorectal cancer. in Jordan We examined 90 tissue samples previously diagnosed with colorectal carcinoma, and 56 non-cancerous colon tissues. DNA was extracted from paraffin embedded tissues and the status of the GSTP1 polymorphism was determined using a polymerase chain reaction restriction fragment length polymorphism (RFLP) method. No statistically significant differences were found between colorectal cancer cases and controls for the GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes. The glutathione S-transferase polymorphism was not associated with risk in colorectal cancer cases in Jordan stratified by age, sex, site, grade or tumor stage. In conclusion, the GSTP1 Ile105Val polymorphism is unlikely to affect the risk of colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

The GSTP1 Ile105Val Polymorphism is not Associated with Susceptibility to Colorectal Cancer

Khabaz

2012

Asian Pacific Journal of Cancer Prevention

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“…Hypermethylation of the GSTP1 CpG island is an early and common event in prostate cancer (Brooks et al, 1998;Cookson et al, 1997;Esteller, 2000;Lee et al, 1994;Millar et al, 1999;Moskaluk et al, 1997). We previously reported that the methylation pattern across the GSTP1 CpG island in the prostate cancer cell line LNCaP is extensive and the gene is silent (Millar et al, 1999(Millar et al, , 2000.…”

Section: Gstp1 Methylation In Lncap and Du145 Cell Linesmentioning

confidence: 99%

“…We previously reported that the methylation pattern across the GSTP1 CpG island in the prostate cancer cell line LNCaP is extensive and the gene is silent (Millar et al, 1999(Millar et al, , 2000. Essentially all the CpG sites are methylated extending past the ATAAA repeat motif through the promoter region and into the body of the gene (Figure 2).…”

Section: Gstp1 Methylation In Lncap and Du145 Cell Linesmentioning

confidence: 99%

“…Therefore, the GSTP1 CpG island becomes an ideal candidate to study what triggers its hypermethylation in prostate cancer cells. We have previously described the methylation pro®le across the CpG island of the GSTP1 gene in normal and prostate cancer cells and found that the gene is extensively methylated and inactivated in prostate cancer cells, including the prostate cancer cell line LNCaP (Millar et al, 1999(Millar et al, , 2000. In contrast, the cancer cell line DU145 behaves more like a normal prostate cell with GSTP1 gene essentially unmethylated and expressed.…”

Section: Introductionmentioning

confidence: 99%

“…The gene is expressed and unmethylated in all normal tissues and is not commonly methylated in other cancers, with exception of liver and breast cancer (Esteller et al, 1998;Jhaveri and Morrow, 1998;Tchou et al, 2000). Intriguingly no mutations or deletions have been reported for GSTP1 in prostate cancer, however the gene is inactivated and both alleles are commonly methylated (Millar et al, 1999). Therefore, the GSTP1 CpG island becomes an ideal candidate to study what triggers its hypermethylation in prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells

et al. 2002

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Understanding what triggers hypermethylation of tumour suppressor genes in cancer cells is critical if we are to discern the role of methylation in the oncogenic process. CpG sites in CpG island promoters, that span most tumour suppressor genes, remain unmethylated in the normal cell, despite the fact that CpG sites are the prime target for de novo methylation by the DNA methyltransferases. The CpG island-associated with the GSTP1 gene is an intriguing example of a CpG rich region which is susceptible to hypermethylation in the majority of prostate tumours and yet is unmethylated in the normal prostate cell. In this study we evaluate a number of factors purported to be involved in hypermethylation to test their role in triggering hypermethylation of GSTP1 in prostate cancer DU145 and LNCaP cells. We ®nd that hypermethylation is not associated with (1) elevated expression of the DNA methyltranferases, or (2) removal of Sp1 transcription factor binding sites in the CpG island or (3) removal of CpG island boundary elements or (4) prior gene silencing. Instead our results support a model that requires a combination of prior gene silencing and random`seeds' of methylation to trigger hypermethylation of the GSTP1 gene in the prostate cancer cell. We propose that the GSTP1 gene is initially silenced in the prostate cancer and random sites of methylation accumulate that result in subsequent hypermethylation and chromatin remodelling.

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DNA methyltransferase levels and altered CpG methylation in the total genome and in the GSTP1 gene in human glioma cells transfected with sense and antisense DNA methyltransferase cDNA

Antoun¹,

Baylin²,

Ali‐Osman³

2000

J. Cell. Biochem.

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This study examines the efficacy of using plasmid expression vectors containing sense and antisense DNA MTase cDNA to both up- and downregulate intracellular DNA MTase levels in human glioma cells. The effects of the changes in MTase levels on global genomic DNA methylation and on the methylation status of CpG dinucleotides in the GSTP1 gene were determined in a glioma cell line that overexpresses the GSTP1 gene. In cells transfected with sense DNA MTase cDNA, MTase gene transcripts increased to a maximum of 2. 5-fold at 24 h, while MTase activity increased to a maximum of 3. 6-fold at 48 h. The effects of antisense MTase cDNA transfections were less pronounced, and levels of MTase gene transcripts and enzyme activity in transfectants were decreased to only, approximately, one-half the levels of controls. The alterations in DNA MTase expression were associated with corresponding changes in the level of global DNA methylation and in the methylation of the GSTP1 gene in the cells, however, with no detectable morphological or cytotoxic effects on the cells. No significant changes in GSTP1 gene expression were detected after the transfections, presumably because of the high levels of basal GSTP1 expression in the cells. Consequently, the p16 gene, known to be repressed transcriptionally by DNA methylation, was examined for the functional effects of the altered MTase levels. The results showed a 2-fold decrease in p16 gene transcripts with the sense MTase transfectants, while in the MTase antisense-transfected cells p16 transcript levels increased by 30%. Together, these results demonstrate the feasibility of using both sense and antisense DNA MTase expression vectors to regulate DNA MTase levels in glioma cells and that, over relatively short periods of time, the alterations in MTase activities are not deleterious to the cells. The system provides a model with which the role of DNA methylation in critical genes and DNA sequences can be investigated in glioma cells.

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Detailed methylation analysis of the glutathione S-transferase π (GSTP1) gene in prostate cancer

Cited by 208 publications

References 31 publications

The GSTP1 Ile105Val Polymorphism is not Associated with Susceptibility to Colorectal Cancer

The GSTP1 Ile105Val Polymorphism is not Associated with Susceptibility to Colorectal Cancer

Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells

DNA methyltransferase levels and altered CpG methylation in the total genome and in the GSTP1 gene in human glioma cells transfected with sense and antisense DNA methyltransferase cDNA

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