Lysine-specific histone demethylase 1A (KDM1A) (KDM1A)

Lysine-specific histone demethylase 1A (KDM1A), also known as LSD1, is a flavin-adenine dinucleotide (FAD)-dependent enzyme that serves as a critical epigenetic regulator by removing methyl groups from histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) (UniProt O60341) [1]. It is an integral component of several transcriptional corepressor complexes, such as CoREST and NuRD, and plays a vital role in maintaining the balance between stem cell self-renewal and differentiation (NCBI Gene 23028) [2]. In many cancers, including acute myeloid leukemia (AML) and small cell lung cancer (SCLC), KDM1A is overexpressed and contributes to the silencing of tumor suppressor genes and the maintenance of an undifferentiated, proliferative state (PubMed: 25730868) [3]. Therapeutic strategies targeting KDM1A primarily utilize small molecule inhibitors that bind to its catalytic domain, thereby restoring the expression of differentiation-related genes and inhibiting tumor growth (PubMed: 29551515) [4]. While the protein is the most common pharmacological target, the KDM1A mRNA transcript itself is also a target for experimental RNA-based therapies, such as siRNAs and antisense oligonucleotides, aimed at reducing the overall cellular pool of the KDM1A enzyme (PubMed: 31105166) [5].

Other names

LSD1AOF2BHC110KDM1Lysine-specific demethylase 1

KDM1A inhibitors primarily act by binding to the flavin-adenine dinucleotide (FAD) pocket of the enzyme, which prevents the demethylation of histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) (PubMed: 25730868). This inhibition leads to the accumulation of activating histone marks (like H3K4me2) at the promoters of target genes, such as those involved in myeloid differentiation (e.g., GFI1B), thereby reversing the transcriptional repression characteristic of certain cancers (PubMed: 29551515). Some inhibitors also disrupt the physical interaction between KDM1A and transcription factors like GFI1 or SNAG-domain proteins, which is essential for their oncogenic function (PubMed: 29551515).