1. Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany
2. Max-Planck-Institut für Immunbiologie, Stübeweg 51, 79108 Freiburg, Germany
3. Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, 4058 Basel, Switzerland
4. Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
5. *These authors contributed equally to this work

Correspondence to: Roland Schüle¹ Correspondence and requests for materials should be addressed to R.S. (Email: roland.schuele@uniklinik-freiburg.de).

Abstract

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor¹. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues². Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110)³ co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.

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