TY - JOUR
T1 - Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor
AU - Willmann, Dominica
AU - Lim, Soyoung
AU - Wetzel, Stefan
AU - Metzger, Eric
AU - Jandausch, Anett
AU - Wilk, Wolfram
AU - Jung, Manfred
AU - Forne, Ignasi
AU - Imhof, Axel
AU - Janzer, Andreas
AU - Kirfel, Jutta
AU - Waldmann, Herbert
AU - Schüle, Roland
AU - Buettner, Reinhard
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012/12/1
Y1 - 2012/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867091498&partnerID=8YFLogxK
U2 - 10.1002/ijc.27555
DO - 10.1002/ijc.27555
M3 - Journal articles
C2 - 22447389
AN - SCOPUS:84867091498
SN - 0020-7136
VL - 131
SP - 2704
EP - 2709
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 11
ER -