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Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A

1
ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, 17007 Girona, Spain
2
Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain
3
StemTek Therapeutics, 48160 Bilbao, Spain
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Department of Analytical Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain
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Research and Development Functional Food Centre (CIDAF), PTS Granada, 18100 Granada, Spain
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Cardiovascular Genetics Centre, Department of Medical Sciences, University of Girona, 17071 Girona, Spain
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Mind the Byte, 08007 Barcelona, Spain
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Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
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Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
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Dr. Josep Trueta Hospital of Girona, 17007 Girona, Spain
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Medical Oncology, Catalan Institute of Oncology (ICO), 17007 Girona, Spain
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Department of Medical Sciences, Medical School University of Girona, 17071 Girona, Spain
13
Institute of Research, Development and Innovation in Biotechnology of Elche (IDiBE) and Molecular and Cell Biology Institute (IBMC), Miguel Hernández University (UMH), 03202 Elche, Spain
*
Author to whom correspondence should be addressed.
Nutrients 2019, 11(7), 1656; https://doi.org/10.3390/nu11071656
Received: 5 July 2019 / Revised: 16 July 2019 / Accepted: 17 July 2019 / Published: 19 July 2019
(This article belongs to the Special Issue Polyphenol-Rich Foods for Human Health and Disease)
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. View Full-Text
Keywords: phenolics; secoiridoids; cancer; cancer stem cells; SOX2; metabolism; neurological disorders phenolics; secoiridoids; cancer; cancer stem cells; SOX2; metabolism; neurological disorders
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Cuyàs, E.; Gumuzio, J.; Lozano-Sánchez, J.; Carreras, D.; Verdura, S.; Llorach-Parés, L.; Sanchez-Martinez, M.; Selga, E.; Pérez, G.J.; Scornik, F.S.; Brugada, R.; Bosch-Barrera, J.; Segura-Carretero, A.; Martin, Á.G.; Encinar, J.A.; Menendez, J.A. Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A. Nutrients 2019, 11, 1656.

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