12,15,41�C45 Interestingly, expression of some of these genes is regulated by DNA methylation at their promoters. In general, selleckchem promoter hypermethylation is associated with the loss of expression of these genes. A spectrum of methods is available for DNA methylation. These include cytosine deamination PCR, semi-quantitative and quantitative methylation-specific PCR (MSP), differential methylation hybridization (DMH), restriction landmark genomic scanning (RLGS), single-nucleotide primer extension (SNuPE), pyrosequencing, and methylation microarray for large-scale genome analysis.15,46 However, MSP is a simple and sensitive method, and is the most commonly employed method for methylation analysis.15 Table 1 shows some common genes that are hypermethylated in the prostate cancer and are tested for the development of early detection.
These genes participate in DNA damage repair (GSTP1, MGMT), cell adhesion (CD44, EDNRB, ECADHERIN, APC, LGALS3), cell growth, invasion and metastasis (TIMP2, TIMP3, LGALS3), apoptosis (DAPK), cell cycle control (CDKN2A, CDKN1A), signal transduction (RASSF1A), and hormonal responses (AR, ER, RAR��2).12,15,41�C45 Table 1. Summary of genes whose promoters are frequently methylated in prostate cancer. The glutathione S transferases (GSTs) are a family of enzymes involved in protecting cells from DNA damage, and thence cancer initiation. GSTs carry out intracellular detoxification of xenobiotics and carcinogens by covalent bonding to glutathione via a thiol link.
47 In humans, six cytosolic isoforms of GST (alpha, mu, pi, sigma, theta, and omega) and one membrane isoform of GST have been described- of which the pi isoform (GSTP1) has been extensively studied.48,49 In prostate cancer, GSTP1 is observed to be silenced by promoter methylation.17,39,50,51GSTP1 promoter methylation has been detected in cancerous as well as prostatic intraepithelial neoplasia (PIN) lesions, whereas it has been rarely detected in normal prostate or BPH tissues.40,52,53 Hypermethylation of GSTP1 was also found in a subset of proliferative inflammatory atrophy (PIA) lesions, which are believed to be tumors precursors.53 Another DNA repair gene O6-Methylguanine-DNA-Methyltransferase (MGMT) was found to be hypermethylated (moderate to high levels) in many cancers including prostate cancer.54,55MGMT removes mutagenic and cytotoxic alkyl adducts from O6-guanine in DNA.
56 However, hypermethylation of this gene promoter results in a loss of function in various cancers including prostate cancer.55,57 CD44, an integral membrane glycoprotein, plays a role in cell adhesion and cell-matrix interactions as a receptor for hyaluronic Dacomitinib acid and osteopontin.58 In prostate cancer, CD44, acts as a metastasis suppressor gene, and its down-regulation is associated with tumor progression and metastasis. Hypermethylation of CpG islands in the promoter region of CD44 results in decreased expression.