.. Although the importance of CpG island www.selleckchem.com/products/baricitinib-ly3009104.html methylation has been demonstrated in cancer, the mechanisms that lead to these changes in cancer are not yet understood. Of three members (DNMT1, DNMT3a, and DNMT3b) of the DNA methyltransferase family, DNMT1 is believed to be primarily involved in the maintenance of CpG methylation.28,29 However, other studies suggest that DNMT3b, independently or in cooperation with DNMT1, also contributes to hypermethylation.30�C32 The suppression of transcription by DNA methylation may occur by either direct inhibition33 or indirect inhibition34 of transcription factor binding. For the latter, a family of proteins known as methyl binding domain (MBD) proteins is believed to specifically bind DNA containing methylated CpG sites.

34 At least three of the five known members of this family (MeCP2, MBD2 and MBD3) have been shown to be associated with large protein complexes containing histone deacetylase (HDAC1 and HDAC2) and chromatin-remodeling (Sin3a and mi-2) activities.35,36 Histone deacetylase (HDAC1 and 2) and chromatin remodeling activities (Mi-2 and Sin3a) produce alterations in chromatin structure that make it refractory to transcriptional activation.37 In addition to the large protein complexes, the MBD proteins may associate with several other complexes involved in transcriptional repression. Recently, MeCP2 was shown to interact with at least two other proteins, c-ski and N-CoR, known to be involved in transcriptional repression.

38 However, Ohm et al recently hypothesize that the stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable gene silencing during tumor initiation and progression.39 As mentioned above, cancer cells exhibit two apparently opposing changes in the DNA methylation pattern: a decrease of DNA methylation in the intronic CpG islands and an increase of DNA methylation in the promoter CpG islands. Recent studies suggest that both changes may play important roles in the tumorigenic process. However, the increased methylation at the promoter CpG islands has been by far the most studied and has a much clearer role in carcinogenesis. Increased CpG island methylation can result in inactivation of many well-characterized tumor suppressor genes (e.g. BRCA1, breast cancer 1 gene) as well as inactivation of DNA repair genes, resulting in increased levels of genetic damage. The most striking example is the pi isoform of glutathione S-transferase (GSTP1), which Brefeldin_A is involved in detoxification of potentially DNA-damaging electrophiles.40 Hypermethylated Genes in Prostate Cancer In prostate cancer, a large number of genes (e.g.