85 Its inactivation leads to the loss of this important apoptotic pathway. Although different mechanisms may affect DAPK inactivation in cancer, it has been shown that aberrant methylation sellectchem is mainly responsible for silencing of the DAPK gene; inactivation of DAPK by promoter methylation has been observed in prostate cancer and BPH samples, but not in PIN samples.75,82,86 Cell cycle genes such as retinoblastoma protein (RB), cyclins, cyclin dependent kinases (CDKs), and CDK inhibitors (CDKIs) are very important in regulation of the cell cycle. In cancer, the efficacy of cell cycle checkpoints is often affected, especially control of the G1/S transition.87 CDKIs are negative regulators of the cell cycle and considered to be tumor suppressor genes.

CDKIs are categorized into two families, the INK4 family and the CIP/KIP (kinase inhibitor protein) family. The INK4 family is composed of four members CDKN2A or p16, CDKN2B or p15, CDKN2C or p18, and CDKN2D or p19.88 The CIP/KIP family includes CDKN1A or p21, CDKN1B or p27, and CDKN1C or p57.89 While the INK4 family specifically inhibits CDKs 4 and 6, the CIP/KIP family inhibits most CDKs.88,89 In prostate cancer, cell cycle checkpoint genes can be inactivated by a number of mechanisms such as deletion, point mutation, and hypermethylation. For example, cyclin D2 promoter methylation has been detected in prostate cancer and correlated with disease progression.90 However, other cell cycle genes such as p21 and p27 are rarely methylated in prostate tumors.

91,92 Decreased expression of another negative cell cycle regulator 14-3-3sigma (SFN) due to promoter methylation has been detected in many cancers including prostate tumor and BPH.93,94 Interestingly, in prostate cancer tissues, p16 methylation has been frequently detected in exon 2 rather than in the promoter.54 RAS proteins are involved in extra-cellular signal transduction and regulate cell growth, survival and differentiation.95 A new family of genes encoding RAS-binding proteins, RAS association domain family 1 gene (RASSF1), has been identified as a tumor suppressor in many carcinomas.96 The RASSF1 gene produces two predominant transcripts, RASSF1A and RASSF1C, that are regulated by distinct CpG promoter elements.97 These transcripts are present in normal human tissues, but RASSF1A has been found to be inactivated in some prostate and other cancers.

96,98,99 Inactivation of RASSF1A at different stages of prostate cancer development is correlated with RASSF1A promoter methylation.75,86,100 Androgens such as testosterone and 5��-dihydrotestosterone are the main steroid hormones in the prostate and act through the androgen receptor Drug_discovery (AR).101 The expression of the AR gene and androgen dependence is consistent with the early stages of prostate cancer.