Roles of Glutathione-s-transferase P1 (gstp1) Gene, in Prostate Cancer Detection

Prostate cancer is the leading cause of cancer related death in most developed countries, and is the most common malignancy in males. Early detection of prostate cancer, multiple biopsies, and improved treatment currently represent the most critical strategies to decrease prostate cancer mortality. The development of prostate cancer is a multi-step process through a series of morphologically distinct lesions initiated by genetic and epigenetic changes. DNA methylation is a covalent chemical modification resulting in the addition of a methyl group (CH3) group at the carbon 5 position of the cytosine ring. Even though most cytosine methylation occurs in the sequence context 5CG3 (also called the CpG dinucleotide) some involves CpA and CpT dinuleotides [1].DNA is made up of four bases, thus there are 16 possible dinucleotide combinations that occur.The human genome is not methylated uniformly and contains regions of unmethylated segments interspersed by methylated regions [2]. In contrast to the rest of the genome, smaller regions of DNA, called CpG islands ranging from 0,5 to 5 kb and occurring on average every 100 kb, have distinct properties. DNA methylation is brought about by a group of enzymes known as the DNA methyltransferases (DNMT). The DNMTs known to date are DNMT1, DNMT1b, DNMT10 DNMT1p, DNMT2, DNMT3A, DNMT3b, with its isoforms, and DNMT3L [3]. In addition to the DNMTs, the other machinery of methylation includes demethylases, methylation centers triggering DNA methylation, and methylation protection centers [4, 5] The best characterised gene found to be hypermethylated in prostate cancer is GSTP1, encoding the -class glutathione S-transferase (GST), an enzyme capable of detoxifying electrophilic and oxidant carcinogenesis. Methylation is highly tumour-specific but also prevalent in high-grade prostatic intraepithelial neoplasia lesions, which makes GSTP1 an attractive early detection biomarker. Hypermethylation and inactivation of genes involved in DNA repair, such as GSTP1, may serve as initiating genome lesions for tumour development by increasing susceptibility to carcinogens, thus predisposing to further mutations and DNA damage. GSTP1 functions in the conjugation and detoxification of potential carcinogens and has been demonstrated to have ‘’caretaker activities’’. Promoter hypermethylation accompanied by loss of GSTP1 is one of the earliest and most common somatic genome alterations in prostate cancer. Elevated GSTP1 expression (defending against oxidative genomic damage) is characteristic of proliferative inflammatory atrophy loss of GSTP1 activity in a subset of lesions may promote transformation to high-grade prostatic intraepithelial neoplasia and /or adenocarcinoma.