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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We thank T. Benzing, F. Claessens, T. Jenuwein, Z. Sun and D. Trono for providing reagents. We are obliged to the members of the Schüle laboratory for discussions. We thank K. Fischer, P. Kahl and L. Heukamp for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe to R.S.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Contains Supplementary Methods (plasmids, immunofluorescence, in vitro pull-down assays, mRNAanalyses, tandem affinity purification) and the legends for the Supplementary Figures. (DOC 41 kb)
a, Coomassie blue staining reveals that LSD1 (arrow) is co-purified with TAP-FHL2 (arrow) during tandem affinity purification. b, Western blot analysis using -LSD1 antibody. (PDF 113 kb)
LSD1 expression analyses. (PDF 88 kb)
LSD1 interacts with chromatin. (PDF 82 kb)
LNCaP cells were incubated with or without R1881 and treated with or without pargyline. (PDF 229 kb)
siRNA mediated knockdown of LSD1. (PDF 52 kb)
Specificity of LSD1 in the control of AR-induced transcriptional activity. (PDF 15 kb)
Specificity of LSD1 in the control of AR-induced transcriptional activity. (PDF 8 kb)
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Metzger, E., Wissmann, M., Yin, N. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005). https://doi.org/10.1038/nature04020
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