Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 131, Issue 11, Pages 2704-2709Publisher
WILEY-BLACKWELL
DOI: 10.1002/ijc.27555
Keywords
LSD1; inhibitor; prostate cancer; chromatin-modifying enzyme; demethylation
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Funding
- Deutsche Krebshilfe
- Deutsche Forschungsgemeinschaft [Schu688/12-1, 11-1, 9-1, SFB746/P2, Ju 295/7-1, GRK804, FP7 ERC 268309]
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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.
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