Abstract
The lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a central epigenetic regulator of metabolic reprogramming in obesity-associated diseases, neurological disorders, and cancer. Here, we evaluated the ability of oleacein, a biophenol secoiridoid naturally present in extra virgin olive oil (EVOO), to target LSD1. Molecular docking and dynamic simulation approaches revealed that oleacein could target the binding site of the LSD1 cofactor flavin adenosine dinucleotide with high affinity and at low concentrations. At higher concentrations, oleacein was predicted to target the interaction of LSD1 with histone H3 and the LSD1 co-repressor (RCOR1/CoREST), likely disturbing the anchorage of LSD1 to chromatin. AlphaScreen-based in vitro assays confirmed the ability of oleacein to act as a direct inhibitor of recombinant LSD1, with an IC50 as low as 2.5 μmol/L. Further, oleacein fully suppressed the expression of the transcription factor SOX2 (SEX determining Region Y-box 2) in cancer stem-like and induced pluripotent stem (iPS) cells, which specifically occurs under the control of an LSD1-targeted distal enhancer. Conversely, oleacein failed to modify ectopic SOX2 overexpression driven by a constitutive promoter. Overall, our findings provide the first evidence that EVOO contains a naturally occurring phenolic inhibitor of LSD1, and support the use of oleacein as a template to design new secoiridoid-based LSD1 inhibitors.
Highlights
Natural biophenols in extra virgin olive oil (EVOO), a health-promoting ingredient of the so-called Mediterranean Diet, have been proposed to have multifaceted and beneficial effects on major diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative disease, and metabolic disorders [1,2,3,4,5,6,7,8,9]
We performed a molecular mechanics/generalized born surface area (MM/GBSA) approximation of the oleacein–lysine-specific histone demethylase 1A (LSD1) binding affinity, which considers the dynamic nature of LSD1 and provides a more realistic view of oleacein binding affinity than the aforementioned rigid rocking estimations
N-terminal region [49,50], we cannot exclude the possibility that higher concentrations of oleacein might target LSD1 via a scaffolding/structural mechanism involving disruption of the chromatin-binding activity of the LSD1/RCOR1/CoREST complex
Summary
Natural biophenols in extra virgin olive oil (EVOO), a health-promoting ingredient of the so-called Mediterranean Diet, have been proposed to have multifaceted and beneficial effects on major diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative disease, and metabolic disorders [1,2,3,4,5,6,7,8,9]. Endogenous ligands and assign molecular functions to the biophenol oleacein [12]—one of the most abundant secoiridoids in EVOO that seems to be largely responsible for its health-promoting effects [6]. Our virtual profiling approach employing structure-based tools revealed a target landscape of oleacein significantly enriched in metabolic and chromatin-modifying enzymes involved in histone post-translational modification. Among the latter group was lysine-specific demethylase-1 (LSD1, known as KDM1A), a flavin adenine dinucleotide (FAD)-dependent homolog of the amine oxidase family that was originally described to target histone H3K4 [13,14]. LSD1 has been linked to a repression of gene expression, and was later reported to interact with the androgen or estrogen receptor to demethylate histone H3K9 [15,16,17], resulting in the activation of gene expression
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