title: Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives.
abstract: Lysine-specific demethylase 1 (LSD1) is upregulated in many cancers, especially neuroblastoma. We set out to explore whether geranylgeranoic acid (GGA) inhibits LSD1 activity by using recombinant human LSD1. GGA inhibited LSD1 activity with IC50 similar to that of the clinically used drug tranylcypromine. In human neuroblastoma SH-SY5Y cells, GGA induced NTRK2 gene expression alongside upregulation of histone H3 with dimethylated lysine-4 in the regulatory regions of the NTRK2 gene. Dihydrogenation of GGA reinforced the LSD1-inhibitory effect in a position-dependent manner. The inhibitory effects of dihydro-derivatives of GGA on recombinant LSD1 strongly correlated with the induction of NTRK2 gene expression in SH-SY5Y cells. These data demonstrate for the first time the efficient LSD1-inhibitor activity of GGA and its derivatives, providing a novel prospect of preventing cancer onset by using GGA to regulate epigenetic modification.
authors.affiliation: Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Nagayo, Nagasaki 851-2195, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sakane
authors.affiliation: Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okitsu
authors.affiliation: Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
authors.forename: Akimori
authors.initials: A
authors.lastname: Wada
authors.affiliation: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Miyagi 980-8577, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sagami
authors.affiliation: Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Nagayo, Nagasaki 851-2195, Japan. Electronic address: shidoji@sun.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shidoji
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005204:Farnesol / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020813:Receptor, trkB / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D004224:Diterpenes; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014191:Tranylcypromine; D005204:Farnesol; C040155:geranylgeranic acid; D056466:Histone Demethylases; C495195:KDM1A protein, human; D020813:Receptor, trkB
keywords: Epigenetics; Geranylgeranoic acid; Lysine-specific demethylase; Neuroblastoma