Universität zu Köln

Willmann, Dominica, Lim, Soyoung, Wetzel, Stefan, Metzger, Eric, Jandausch, Anett, Wilk, Wolfram, Jung, Manfred ORCID: 0000-0002-6361-7716, Forne, Ignasi, Imhof, Axel ORCID: 0000-0003-2993-8249, Janzer, Andreas, Kirfel, Jutta, Waldmann, Herbert ORCID: 0000-0002-9606-7247, Schuele, Roland and Buettner, Reinhard (2012). Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor. Int. J. Cancer, 131 (11). S. 2704 - 2710. HOBOKEN: WILEY-BLACKWELL. ISSN 0020-7136

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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 ?-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Willmann, Dominica UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, Soyoung UNSPECIFIED UNSPECIFIED UNSPECIFIED Wetzel, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Metzger, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Jandausch, Anett UNSPECIFIED UNSPECIFIED UNSPECIFIED Wilk, Wolfram UNSPECIFIED UNSPECIFIED UNSPECIFIED Jung, Manfred UNSPECIFIED orcid.org/0000-0002-6361-7716 UNSPECIFIED Forne, Ignasi UNSPECIFIED UNSPECIFIED UNSPECIFIED Imhof, Axel UNSPECIFIED orcid.org/0000-0003-2993-8249 UNSPECIFIED Janzer, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldmann, Herbert UNSPECIFIED orcid.org/0000-0002-9606-7247 UNSPECIFIED Schuele, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-477990
DOI:	10.1002/ijc.27555
Journal or Publication Title:	Int. J. Cancer
Volume:	131
Number:	11
Page Range:	S. 2704 - 2710
Date:	2012
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	0020-7136
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HISTONE DEMETHYLATION; SILENCED GENES; LSD1; ANALOGS; TRANS-2-PHENYLCYCLOPROPYLAMINE; REEXPRESSION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47799