Epigenetic regulation in bladder cancer: development of new prognostic targets and therapeutic implications

Bladder cancer is one of the leading cancers of the urinary tract. It is often diagnosed at advanced stages of the disease and high rates of recurrence are the most difficult obstacle for patient treatment (1). To explore early diagnostic and possible therapeutic targets for bladder cancer, understanding the regulatory system of gene expression is one of the most significant steps. Among many transcriptional regulatory mechanisms, modulation of epigenetic modifications has been studied most extensively over the last decade. Epigenetic modifications to DNA or its associated proteins result in changes in gene expression without altering DNA sequences (2). These characteristics make regulation of epigenetic mechanisms more flexible and important therapeutic targets for cancer treatments. Epigenetic regulatory modification includes DNA methylation alterations to gene promoter regions, histone modifications, and microRNA (miRNA) expression changes. DNA methylation is an enzymatic process involving covalent modifications of DNA with methyl groups using S-adenosyl methionine (SAM) as the methyl group donor and addition of this moiety to the 5-carbon atom of the cytosine base. DNA methylation typically acts to repress gene transcription. In plants and other organisms, DNA methylation is generally found in three different sequence contexts: CG (or CpG), CHG, or CHH (where H corresponds to A, T, or C). In mammals, however, DNA methylation almost exclusively occurs at CpG dinucleotide sites, with the cytosine on both strands usually being methylated. The DNA methylation process is known to be associated with development, aging, and carcinogenesis (3). In tumorigenesis, hypermethylation of tumor suppressor genes and hypomethylation of oncogenes have been characterized. Histone modification includes acetylation, methylation, carbonylation, ubiquitination, SUMOylation, and phosphorylation of histone side chains (4). The functional unit of chromatin, the nucleosome, consists of four histone proteins identified as H2A, H2B, H3, and H4. Each of these proteins exhibit ‘tail’ extensions and these can be modified by a number of histone modifying enzymes. The addition of specific chemical groups to histone tails usually alters the binding affinity of the tails to DNA and results in changes in the conformation of the chromatin structure to regulate RNA transcription of genes. Histone acetylation usually indicates active gene transcription, whereas histone methylation is associated with both gene repression and activation, depending on the specific target histone residues. In