Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A.
Elisabet CuyàsJuan GumuzioJesús Lozano SánchezDavid CarrerasSara VerduraLaura Llorach-ParesMelchor Sanchez-MartinezElisabet SelgaGuillermo Javier PérezFabiana S ScornikRamon BrugadaJoaquim Bosch-BarreraAntonio Segura-CarreteroÁngel G MartinJosé Antonio EncinarJavier A MenendezPublished in: Nutrients (2019)
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.
Keyphrases
- transcription factor
- dna methylation
- molecular docking
- type diabetes
- stem cells
- metabolic syndrome
- physical activity
- induced apoptosis
- cell death
- molecular dynamics simulations
- dna damage
- skeletal muscle
- body mass index
- minimally invasive
- high resolution
- brain injury
- long non coding rna
- subarachnoid hemorrhage
- cell cycle arrest
- genome wide identification