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Histone demethylases as a target for cancer therapy

Cancer is a leading cause of death among people aged 45–64 and is responsible for 25 % of all deaths in the EU. There is a high demand for novel and targeted cancer therapy.
Histone demethylases as a target for cancer therapy
Recent studies have revealed that chemical modifications to DNA and histones (proteins that package and order the DNA into structures called nucleosomes) have the potential to activate or repress genes. Therefore, the enzymes that regulate histone modifications are potential targets for directed cancer therapies. The EU-funded project 'A chemical genetics approach towards cancer therapy targeting histone demethylases' (HISTONE DEMETHYLASES) project was initiated to validate certain enzymes. More specifically, researchers will validate histone demethylases (HDs), which remove methyl groups from histones, as potential cancer therapy targets.

Scientists successfully identified inhibitory cyclic peptides that are highly selective for HDs that can remove the so-called H3K36me3 histone mark, the modification of which is associated with the activation of genes. They were able to elucidate the origin of this unprecedented selectivity of one inhibitor by co-crystallising it with the HD. It was found that modifications of lipophilicity and increase in stability can yield cyclic peptides that do cross both the cellular and nuclear membranes.

In a final step, the effect of HD inhibition in cells was investigated by measuring the proliferation rate of different cancer cell lines. All cells treated with the peptides showed reduced growth rate, reflecting the importance of histone H3K36 demethylation for normal cell growth. Staining of cell nuclei suggested that the cells were locked in one phase of the cell cycle, consistent with an important role of HDs in the regulation of gene expression.

In conclusion, the project discovered potent and selective inhibitors for a specific sub-family of HDs. Initial results in cell-based assays suggested that the HDs could be valid targets for cancer therapy as the growth of the cells was inhibited. Altogether, the study could lead to a novel cancer therapy, from which patients in the EU and the whole world would greatly benefit.

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