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Epigenetic Regulation of Gene Expression as an Anticancer Drug Target

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Epigenetic processes play a key regulatory role in cancer. Hypermethylation in the CpG islands of the promoter regions of many tumour suppressor genes leads to the recruitment of co-repressors, altered chromatin structure, and ultimately transcriptional silencing. Key components in the regulation of DNA methylation are DNA methyltransferases (DNMT1, 2, 3A and 3B) and methyl CpG-binding proteins, which recognize methyl cytosine residues and recruit transcriptional repressor complexes, including histone deacetylases (HDAC). DNMT1 is responsible for the maintenance of DNA methylation patterns during replication. Inhibitors of this enzyme may potentially lead to DNA hypomethylation, and re-expression of tumour suppressor genes. Several DNMT inhibitors are currently being evaluated in preclinical and clinical studies, which include various analogues of adenosine, cytidine or deoxycytidine. However, such drugs have had limited clinical success, perhaps because of cytotoxicity associated with their incorporation into DNA. Non-nucleoside small molecule inhibitors of DNMTs can directly block DNMT activity, and may be able to circumvent this cytotoxicity. Post-translational modifications of histones play a key role, not only in regulating chromatin structure and gene expression, but also in genomic stability. Histone acetylation (HAT) and histone deacetylation (HDAC) affect chromatin condensation, with concomitant effects on gene transcription. A further range of compounds is being evaluated for clinical use as HDAC inhibitors, including hydroxamic acids such as Trichostatin A (TSA) and Suberoyl anilide bishydroxamide (SAHA). MicroRNAs are also found to play a key role in cancer development, and novel approaches to their regulation may provide a susceptible anticancer drug target. Because of the interdependence of epigenetic processes, combinations of these approaches may have maximum clinical efficacy.

Keywords: DNA hypomethylation; DNA methylation; DNA methyltransferases; Epigenetics; Histone acetylation; Hypermethylation; Nuclear factor kappa B; S-adenosyl-methionine SA; Streptomyces; Suberoyl anilide bishydroxamide; Trichostatin A; Valproic; Zebularine; adenosine, cytidine; aminobenzoic; antitumour agents; apoptosis; benzamide; benzamides; carcinogenesis; chromatin; chronic myeloid leukaemia; cutaneous T-cell lymphoma; de-rivatives; deoxycytidine; dinucleotide; disulfides; gastrointestinal cancers; histone acetyl transferases; histone deacetylase inhibitor; histone deacetylases; hydrazines; leukemia; mesothelioma demonstrated; methyl transferase; methyltransferase inhibitor; methyltransferases; microRNA; morphogenesis; myelodysplastic syndrome; nucleosomes; phthalides; polyphenols; transcription factors

Document Type: Research Article

Publication date: February 1, 2011

More about this publication?
  • Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes, genes.
    Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cancer.
    As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.

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