Letter abstract
Nature Cell Biology 9, 347 - 353 (2007)
Published online: 4 February 2007 | doi:10.1038/ncb1546
Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression
Melanie Wissmann1, Na Yin1, Judith M. Müller1, Holger Greschik1, Barna D. Fodor2, Thomas Jenuwein2, Christine Vogler3, Robert Schneider3, Thomas Günther1, Reinhard Buettner4, Eric Metzger1 & Roland Schüle1
Posttranslational modifications of histones, such as methylation, regulate chromatin structure and gene expression1. Recently, lysine-specific demethylase 1 (LSD1)2, the first histone demethylase, was identified. LSD1 interacts with the androgen receptor and promotes androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9)3 only. Here, we identify the Jumonji C (JMJC)4 domain-containing protein JMJD2C5, 6 as the first histone tridemethylase regulating androgen receptor function. JMJD2C interacts with androgen receptor in vitro and in vivo. Assembly of ligand-bound androgen receptor and JMJD2C on androgen receptor-target genes results in demethylation of trimethyl H3K9 and in stimulation of androgen receptor-dependent transcription. Conversely, knockdown of JMJD2C inhibits androgen-induced removal of trimethyl H3K9, transcriptional activation and tumour cell proliferation. Importantly, JMJD2C colocalizes with androgen receptor and LSD1 in normal prostate and in prostate carcinomas. JMJD2C and LSD1 interact and both demethylases cooperatively stimulate androgen receptor-dependent gene transcription. In addition, androgen receptor, JMJD2C and LSD1 assemble on chromatin to remove methyl groups from mono, di and trimethylated H3K9. Thus, our data suggest that specific gene regulation requires the assembly and coordinate action of demethylases with distinct substrate specificities.
- Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.
- Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr. Bohrgasse 7, 1030 Vienna, Austria.
- Max-Planck-Institut für Immunbiologie, Stübeweg 51, 79108 Freiburg, Germany.
- Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
Correspondence to: Roland Schüle1 e-mail: roland.schuele@uniklinik-freiburg.de
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