LSD1: more than demethylation of histone lysine residues

Bruno Perillo,Alfonso Tramontano,Antonio Pezone,Antimo Migliaccio

doi:10.1038/s12276-020-00542-2

Abstract

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.

Highlights

Nucleosomal histones (H2A, H2B, H3, and H4) are extensively involved in DNA supercoiling and chromosomal positioning within the nuclear space
The C-terminal domain is split into two fragments by the Tower domain: the left side essentially binds the flavin adenine dinucleotide (FAD) cofactor, while the right side interacts with SWIRM and forms a cavity that represents the catalytic pocket of Lysine-specific histone demethylase 1 (LSD1)
The Tower domain protrudes from this spherical protein core and forms a slim helix-turn-helix motif that provides the binding site for the SWI3/ADA2/ N-CoR/TFIIIB (SANT) 2 domain in the corepressor for element-1-silencing transcription factor (CoREST) complex that, in turn, facilitates LSD1 tethering to the nucleosomal substrate[15], which is wedged by the Tower domain itself[16]

Summary

Introduction

Nucleosomal histones (H2A, H2B, H3, and H4) are extensively involved in DNA supercoiling and chromosomal positioning within the nuclear space. CoREST complexes enclose histone deacetylases 1/2 (HDAC1/2) and the plant homeodomain (PHD) finger protein BHC80: in this way, they combine two transcriptional inhibitory factors (LSD1 and HDAC1/2), with LSD1 activity, which is positively influenced by HDAC-induced deacetylation that increases affinity of the entire complex for chromatin, promoting the remove of methyl marks from target lysine residues by demethylase[26,27].

Results

Conclusion