Epigenetic regulation constitutes a fundamentally important set of gene control mechanisms that profoundly influence chromatin function, with direct relevance to a large number of human diseases. Histone lysine methylation and demethylation are components of a histone code, and the recognition of these methyl marks underlies epigenetic regulation. For example, overexpression of a histone lysine demethylase, PHF8, has been noted in primary prostate cancer samples, where it is associated with increased invasiveness and a poorer prognosis. The inherently reversible nature of epigenetic modifications makes enzymes that modify histones and DNA attractive candidates for therapeutic intervention. Thus far such epigenetic therapies have focused on the enzymes that regulate histone acetylation and DNA methylation, with several HDAC and DNMT inhibitors now in clinical use and FDA approved for the treatment of leukemias and other cancers. The enzymes involved in regulating histone methylation patterns and levels have emerged as highly promising therapeutic targets, with newer histone methyltransferase inhibitors recently entering preclinical testing. Histone lysine demethylases (belong to a broad family of non-heme Fe(II)-dependent dioxygenases), on the other hand, remain a relatively untapped source of potential druggable targets. The central goal of this proposal is to validate, re-design, and synthesize small molecule inhibitors of histone lysine demethylases in vitro, and to investigate the mechanism(s) of inhibition by nature (iso)flavone derivatives.

Public Health Relevance

It is now well established that cancer arises in part from an altered epigenome, with widespread alterations in DNA methylation and chromatin modifications contributing to altered gene expression programs and contributing to a progressive loss of genome stability. Although the precise molecular mechanisms underlying these events remain unclear, the observation that many epigenetic regulators, including the DNA (hydroxy)methyltransferases, histone lysine methyltransferases and demethylases are targets of somatic mutations and/or are misexpressed in human cancers suggests that epigenetic dysregulation is not simply a characteristic of cancer cells, but may play a more direct role (as 'driver gene' mutations) in the development and progression of the disease. Our preliminary data indicate that natural isoflavone compounds (such as genistein and daidzein) and flavone compounds (such as luteolin and baicalein) function as inhibitors of two histone demethylases in vitro and the availability of hundreds of (iso)flavone derivative compounds provides us with the opportunity to discover potential pharmaceutical reagents that could link inhibition of histone methylation with possible mechanism(s) of action of these natural compounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function C Study Section (MSFC)
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Preusch, Peter
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Emory University
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