2. Academic Validation
  3. Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives

Inhibition of lysine-specific demethylase 1 by the acyclic diterpenoid geranylgeranoic acid and its derivatives

  • Biochem Biophys Res Commun. 2014 Jan 31;444(1):24-9. doi: 10.1016/j.bbrc.2013.12.144.
Chiharu Sakane 1,  Takashi Okitsu 2,  Akimori Wada 2,  Hiroshi Sagami 3,  Yoshihiro Shidoji 4
Affiliations

Affiliations

  • 1 Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Nagayo, Nagasaki 851-2195, Japan.
  • 2 Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
  • 3 Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Miyagi 980-8577, Japan.
  • 4 Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Nagayo, Nagasaki 851-2195, Japan. Electronic address: shidoji@sun.ac.jp.
PMID: 24406160 DOI: 10.1016/j.bbrc.2013.12.144
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.

Keywords

Epigenetics; Geranylgeranoic acid; Lysine-specific demethylase; Neuroblastoma.

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