Histone lysine demethylases in the third decade: biology and therapeutic prospects.

Abstract

Histone post-translational modifications, such as methylation, acetylation, phosphorylation and ubiquitination, have fundamental roles in regulating chromatin structure and gene expression. Histone methylation was once considered a static modification until the discovery of the histone lysine demethylase LSD1 (KDM1A), more than two decades ago. Since then, numerous KDMs in two main enzyme classes have been identified. Their diverse roles in regulating gene expression, metabolism, immune responses and disease pathogenesis have been extensively studied and small-molecule inhibitors have been developed. KDMs exert context-dependent functions as either oncogenes or tumour suppressors, which complicates their therapeutic targeting. As we enter the third decade of investigations into histone demethylation, unlocking the full therapeutic potential of inhibiting KDMs will require a deeper understanding of their biology, substrate specificity, interaction networks and regulatory crosstalk. In this Review, we discuss the functions of KDMs in metabolic and immune regulation and their roles in cancer and other diseases. We describe the landscape of KDM inhibitors, especially LSD1 inhibitors, which are the most advanced demethylase inhibitors in clinical trials. We highlight the need for more potent and selective KDM inhibitors, biomarkers of therapeutic response, novel combinatorial treatments and innovative drug discovery strategies.

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