The past decade has seen a rapid emergence of epigenetics as a major contributor to carcinogenesis. Aberrations in the normal DNA methylation patterns and histone modifications have been recognized as targets for therapy which, unlike conventional chemotherapy, aim to revert the abnormal state of malignant cells to a more normal condition.
Demethylating agents that belong to a group of nucleoside analogues all have cytosine-ring modifications that allow each compound to form a covalent complex with a DNA methyltransferase, thereby inhibiting further methylation. Other DNA-methylation inhibitors belong to a group of non-nucleoside analogues whose mechanism of inhibition is not well known.
DNA methylation inhibitors have the disadvantages of lacking specificity and causing genome-wide hypomethylation which might activate appropriately silent genes and/or initiate genome instability, leading to undesirable consequences. These problems will be circumvented with more specific drugs directed to specific regions of the genome. It is anticipated that these drugs would be available in the form of chemically synthesized small molecules, which are more effective than cytidine analogues because they do not require incorporation into DNA and bind directly to the catalytic site of the DNA methyl transferases.
Histone deacetylase (HDAC) inhibitors are divided into four groups but hybrid molecules combining functional groups with superior inhibitory effects have already been synthesized. Compounds that inhibit individual members of all HDAC classes will be synthesized in the future.
Lysine methylation is another histone modification which could be essential in regulating gene expression but its use as a target for epigenetic therapy might not come to fruition until more complete classification of this type of epigenetic regulation is possible.
The initiation and progression of cancer is controlled by both genetic and epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.
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We are grateful to J. Lin for help with the drawing of a figure and G. Egger, A. Aparicio and A. Yang for proofreading of the manuscript and their valuable comments.
P.A.J. is a consultant to and shareholder of Epigenomics AG and is on the Speakers Bureau for MGI Pharma which is developing decitabine. C.B.Y. does not have any competing financial interest.
Mitotically and meiotically heritable changes in gene expression patterns that are not explained by DNA sequence changes. Epigenetic changes are implicated in many aspects of cell biology including X-inactivation, imprinting, position-effect variegation and, most recently, cancer.
- DNA methylation
A modification to the 5-position of a cytosine ring that occurs most commonly in the context of a CpG palindrome in DNA that can be transmitted to daughter cells at cell division and has been implicated in regulation of gene expression.
- CpG island
A region of DNA that is about 500-bp long with a high GC content and the ratio of observed to expected CpG dinucleotides greater than 0.6, which usually lies near the promoter of a gene and that is unmethylated in the germline.
- Histone methylation
Histone methylation on lysine and arginine residues is mediated by histone lysine methyltransferases (HMTs) and protein arginine methyltransferases (PRMTs), respectively, which transfer a methyl group from S-adenosyl-L-methionine. Lysine residues are mono-, di- or trimethylated and arginines are mono-, symmetric di- or asymmetric dimethylated on their ε-amino groups, and these methyl marks play an important role in chromatin remodelling.
- Histone lysine acetylation
Histones are acetylated on the ε-amino group of lysine residues. Acetyl groups interact with the bromodomain of other proteins, and acetylation of H3 and H4 is implicated in transcriptional activation.
- SET domain
SET (Su(var)39, Enhancer of zeste, Trithorax) domains are protein–protein interacting domains that are associated with methyltransferase activity and function to modulate the chromatin structure.
- Restriction landmark genomic scanning
(RLGS). A quantitative method for measuring the level of DNA methylation in thousands of CpG islands. This technique is especially suited for detection of aberrant DNA methylation and DNA amplifications.
- Androgen receptor
(AR). A member of a family of proteins called nuclear receptors which bind lipophilic steroid molecules. AR interacts with androgens, binds to androgen receptor element (ARE), and causes transcription activation of its target genes; it is a common target of therapy for prostate cancer.
- Uridine/cytidine kinase
An enzyme that catalyses the phosphorylation of uridine and cytidine into uridylate and cytidylate, respectively. It also phosphorylates 5-azacytidine and zebularine into their respective monophosphate moieties.
An enzymatic cofactor and the most important methyl donor in various biological systems. It is involved in both DNA and histone methylation.
A characteristic of many haematological conditions that occurs as a result of abnormal bone marrow function with a likelihood of progressing into acute myelogenous leukaemia.
The comprehensive collection of genome-wide DNA-methylation patterns and chromatin modifications, which gives structure and function to the genome.
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Yoo, C., Jones, P. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5, 37–50 (2006). https://doi.org/10.1038/nrd1930
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