Targeting the LSD1/KDM1 Family of Lysine Demethylases in Cancer and Other Human Diseases

Lysine-specific demethylase 1 (LSD1) was the first histone demethylase discovered and the founding member of the flavin-dependent lysine demethylase family (KDM1). The human KDM1 family includes KDM1A and KDM1B, which primarily catalyze demethylation of histone H3K4me1/2. The KDM1 family is involved in epigenetic gene regulation and plays important roles in various biological and disease pathogenesis processes, including cell differentiation, embryonic development, hormone signaling, and carcinogenesis. Malfunction of many epigenetic regulators results in complex human diseases, including cancers. Regulators such as KDM1 have become potential therapeutic targets because of the reversibility of epigenetic control of genome function. Indeed, several classes of KDM1-selective small molecule inhibitors have been developed, some of which are currently in clinical trials to treat various cancers. In this chapter, we review the discovery, biochemical, and molecular mechanisms, atomic structure, genetics, biology, and pathology of the KDM1 family of lysine demethylases. Focusing on cancer, we also provide a comprehensive summary of recently developed KDM1 inhibitors and related preclinical and clinical studies to provide a better understanding of the mechanisms of action and applications of these KDM1-specific inhibitors in therapeutic treatment.