GSTP1 CpG Island Hypermethylation Is Responsible for the Absence of GSTP1 Expression in Human Prostate Cancer Cells

Abstract

GSTP1CpG island hypermethylation is the most common somatic genome alteration described for human prostate cancer (PCA); lack of GSTP1 expression is characteristic of human PCA cells in vivo. We report here that loss of GSTP1 function may have been selected during the pathogenesis of human PCA. Using a variety of techniques to detect GSTP1 CpG island DNA hypermethylation in PCA DNA, we found only hypermethylated GSTP1 alleles in each PCA cell in all but two PCA cases studied. In these two cases, CpG island hypermethylation was present at only one of two GSTP1 alleles in PCA DNA. In one of the cases, DNA hypermethylation at one GSTP1 allele and deletion of the other GSTP1 allele were evident. In the other case, an unmethylated GSTP1 allele was detected, accompanied by abundant GSTP1 expression. GSTP1 CpG island DNA hypermethylation was responsible for lack of GSTP1 expression by LNCaP PCA cells: treatment of the cells with 5-azacytidine (5-aza-C) , an inhibitor of DNA methyltransferases, reversed the GSTP1 promoter DNA hypermethylation, activated GSTP1 transcription, and restored GSTP1 expression. GSTP1 promoter activity, assessed via transfection of GSTP1 promoter-CAT reporter constructs in LNCaP cells, was inhibited by SssI-catalyzed CpG dinucleotide methylation. Remarkably, although selection for loss of GSTP1 function may be inferred for human PCA,

The role of glutathione-S-transferase in anti-cancer drug resistance

“…The pathology of prostate cancer strongly supports these conclusions. Hypermethylation of the GSTp regulatory region is the most common somatic alteration identified in human prostate cancer (Lin et al, 2001). This alteration results in the loss of GSTp expression, and is proposed to occur during pathogenesis of the disease (Lee et al, 1994).…”

PMP24, a gene identified by MSRF, undergoes DNA hypermethylation-associated gene silencing during cancer progression in an LNCaP model

“…These genes include RARb2 (Nakayama et al, 2001), ER-a (Lau et al, 2000), pS2 (Lau et al, 2000), androgen receptor (Jarrard et al, 1998;Nakayama et al, 2000), AR-associated-protein 70 (ARA70; Tekur et al, 2001), g-glutamyltransferase (GMT; el Yaagoubi et al, 1998), E-cadherin (E-cad; Graff et al, 1995), P-cad (Jarrard et al, 1997a), RASSF1A (Kuzmin et al, 2002), p16 (Jarrard et al, 1997b), glutathione-S-transferase-Pi (GSTPi; Nelson et al, 1997;Lin et al, 2001;Singal et al, 2001), p14 ARF (Esteller et al, 2000), p27 kip1 (Kibel et al, 2001), progesterone receptor (Lau et al, 2000), caveolin-1 and a-subunit of inhibin (Schmitt et al, 2002), and CD44 (Lou et al, 1999;Verkaik et al, 1999). The biological roles of these genes are diverse; they are all involved in the regulation of basic homeostatic cell mechanisms such as cell cycle regulation, cell-cell interaction, protection against oxidative damage, or tumor suppression.…”

Frequent hypermethylation of the RASSF1A gene in prostate cancer

“…The most frequent genomic alteration, thus far detected, is hypermethylation of the GSTP1 promoter region (490%) in prostate carcinoma (Lee et al, 1994). It has been demonstrated that methylation of the GSTP1 promoter region results in loss of expression of GSTP1 in prostate cancer cells (Singal et al, 2001;Lin et al, 2001). The methylation status of GSTP1 is currently used in clinical trials to act as a promising diagnostic marker for prostate carcinoma in the United States (Goessl et al, 2001;Cairns et al, 2001).…”