Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.

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Histone Demethylase JMJD