61 The methylation profile of CD44 was found to be an independent predictor of biochemical recurrence (associated with 9-fold increased risk). This finding, if validated in larger studies, may identify patients with aggressive cancer. The endothelin peptides consisting of three isotypes, ET-1, ET-2, and ET-3 have potent vasoconstructive properties thing and are differentially expressed in various cells and tissues.62 Two receptors for endothelin peptides (ETA and ETB) have been identified in various cells and tissues. Belonging to a family of hyptohelical G-protein-coupled receptors, they are differentially expressed during prostate cancer progression and also differ in binding the enothelin isotypes.63,64 ETA binds to two isotypes ET-1 and ET-2 only, whereas ETB binds to all three isotypes ET-1, ET-2, and ET-3.

63 In prostate cancer, expression of ETA is increased, whereas expression of ETB is reduced.65 Moreover, the ETB gene (EDNRB) is frequently methylated in prostate cancer samples, but to a less so in benign samples.66�C68 E-cadherin, a transmembrane glycoprotein and a member of the cadherin family of cell adhesion molecules, may function as a tumor suppressor gene in invasion and metastasis by mediating cell-cell adhesion via calcium-dependent interactions.69 In prostate cancer, expression of E-cadherin is decreased during tumor progression and this decreased expression has been correlated with hypermethylation of the promoter in patients biopsies.70,71 However, in metastatic prostate cancer cells in bone, E-cadherin expression is increased.

72 Interestingly, the promoter of E-cadherin gene (CDH1) is found unmethylated in the metastatic prostate cancer cells.72 The adenomatous polyposis coli (APC) is a multi-functional protein that acts as a tumor suppressor gene in familial adenomatous polyposis.73 It plays a role in the Wnt signaling pathway, cell migration, cell adhesion, and mitosis.74 In prostate cancer Dacomitinib development, APC hypermethylation has been observed in early cancer stages and in more than 30% of PIN samples.75,76 The methylation frequency becomes higher as the disease progresses.75,77 However, hypermethylation of the APC promoter was also observed in BPH tissues.78 Tissue inhibitors of metalloproteinases (TIMPs) are known to control the activity of matrix metalloproteinases (MMPs)79 in several biological processes such as cell growth, apoptosis, invasion, metastasis and angiogenesis.80,81 Four members of TIMPs have been identified and are known to be down-regulated in prostate cancer.82,83 Down-regulation of TIMP proteins is associated with hypermethylation of the corresponding gene promoters.84 In particular, low-level methylation of TIMP2 and TIMP3 promoters has been detected in prostate carcinoma as well as in BPH.