title: Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor.
abstract: Post-translational modifications of histones by chromatin modifying enzymes regulate chromatin structure and gene expression. As deregulation of histone modifications contributes to cancer progression, inhibition of chromatin modifying enzymes such as histone demethylases is an attractive therapeutic strategy to impair cancer growth. Lysine-specific demethylase 1 (LSD1) removes mono- and dimethyl marks from lysine 4 or 9 of histone H3. LSD1 in association with the androgen receptor (AR) controls androgen-dependent gene expression and prostate tumor cell proliferation, thus highlighting LSD1 as a drug target. By combining protein structure similarity clustering and in vitro screening, we identified Namoline, a γ-pyrone, as a novel, selective and reversible LSD1 inhibitor. Namoline blocks LSD1 demethylase activity in vitro and in vivo. Inhibition of LSD1 by Namoline leads to silencing of AR-regulated gene expression and severely impairs androgen-dependent proliferation in vitro and in vivo. Thus, Namoline is a novel promising starting compound for the development of therapeutics to treat androgen-dependent prostate cancer.
authors.affiliation: Urologische Klinik/Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Dominica
authors.initials: D
authors.lastname: Willmann
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lim
authors.forename: Stefan
authors.initials: S
authors.lastname: Wetzel
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.forename: Anett
authors.initials: A
authors.lastname: Jandausch
authors.forename: Wolfram
authors.initials: W
authors.lastname: Wilk
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Ignasi
authors.initials: I
authors.lastname: Forne
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.forename: Andreas
authors.initials: A
authors.lastname: Janzer
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000728:Androgens; D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D011753:Pyrones; D011944:Receptors, Androgen; D056466:Histone Demethylases; C495195:KDM1A protein, human