LSD1: more than demethylation of histone lysine residues

Cancer: Enzyme modifying chromosomal proteins needs closer examination Further research into the complex structure and behavior of an enzyme involved in gene regulation could improve future cancer therapies. The modification of chromosomal proteins known as histones can fundamentally change gene expression and influence the progression of diseases such as cancer. Bruno Perillo at the Italian National Research Council, Naples, Italy, and co-workers reviewed understanding of the structurally complex enzyme lysine-specific histone demethylase 1 A (LSD1), which interacts with multiple targets including histones. LSD1 removes methyl groups from histones, fine-tuning gene expression and influencing protein activity. The overexpression of LSD1 is linked to cancer development, particularly in aggressive cancers, and inhibiting LSD1 has shown promise in slowing progression and cancer spread. The researchers call for further research into the complexities of LSD1 activity, both in cancers and normal cell function.

Lysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.