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Epigenetic modifications as therapeutic targets

Abstract

Epigenetic modifications work in concert with genetic mechanisms to regulate transcriptional activity in normal tissues and are often dysregulated in disease. Although they are somatically heritable, modifications of DNA and histones are also reversible, making them good targets for therapeutic intervention. Epigenetic changes often precede disease pathology, making them valuable diagnostic indicators for disease risk or prognostic indicators for disease progression. Several inhibitors of histone deacetylation or DNA methylation are approved for hematological malignancies by the US Food and Drug Administration and have been in clinical use for several years. More recently, histone methylation and microRNA expression have gained attention as potential therapeutic targets. The presence of multiple epigenetic aberrations within malignant tissue and the abilities of cells to develop resistance suggest that epigenetic therapies are most beneficial when combined with other anticancer strategies, such as signal transduction inhibitors or cytotoxic treatments. A key challenge for future epigenetic therapies will be to develop inhibitors with specificity to particular regions of chromosomes, thereby potentially reducing side effects.

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Figure 1: Epigenetic aberrations of CpG island promoters in cancer cells and the epigenetic therapies that target them.
Figure 2: Chemical structures of selected compounds that target epigenetic modifications.

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Acknowledgements

Supported by R37CA082422 and R01CA083867 (P.A.J). We thank members of the Jones laboratory for helpful discussions and careful reading of the manuscript, particularly H. Han for help in drawing chemical structures.

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Correspondence to Peter A Jones.

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P.A.J. is a consultant to Lilly and Millipore.

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Kelly, T., De Carvalho, D. & Jones, P. Epigenetic modifications as therapeutic targets. Nat Biotechnol 28, 1069–1078 (2010). https://doi.org/10.1038/nbt.1678

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