Article abstract
Nature Cell Biology 10, 53 - 60 (2008)
Published online: 9 December 2007 | doi:10.1038/ncb1668
There is an Erratum (February 2008) associated with this Article.
Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation
Eric Metzger1, Na Yin1, Melanie Wissmann1, Natalia Kunowska1, Kristin Fischer1, Nicolaus Friedrichs2, Debasis Patnaik3, Jonathan M. G. Higgins3, Noelle Potier4, Karl-Heinz Scheidtmann5, Reinhard Buettner2 & Roland Schüle1
Abstract
Posttranslational modifications of histones such as methylation, acetylation and phosphorylation regulate chromatin structure and gene expression. Here we show that protein-kinase-C-related kinase 1 (PRK1) phosphorylates histone H3 at threonine 11 (H3T11) upon ligand-dependent recruitment to androgen receptor target genes. PRK1 is pivotal to androgen receptor function because PRK1 knockdown or inhibition impedes androgen receptor-dependent transcription. Blocking PRK1 function abrogates androgen-induced H3T11 phosphorylation and inhibits androgen-induced demethylation of histone H3. Moreover, serine-5-phosphorylated RNA polymerase II is no longer observed at androgen receptor target promoters. Phosphorylation of H3T11 by PRK1 accelerates demethylation by the Jumonji C (JmjC)-domain-containing protein JMJD2C. Thus, phosphorylation of H3T11 by PRK1 establishes a novel chromatin mark for gene activation, identifying PRK1 as a gatekeeper of androgen receptor-dependent transcription. Importantly, levels of PRK1 and phosphorylated H3T11 correlate with Gleason scores of prostate carcinomas. Finally, inhibition of PRK1 blocks proliferation of androgen receptor-induced tumour cell proliferation, making PRK1 a promising therapeutic target.
- Universitäts-Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.
- Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
- Institut de Chimie LC3 – CNRS - UMR 7177, ISIS, 8 allée Gaspard Monge, 67083 Strasbourg, France.
- Institut für Genetik, Universität Bonn, Römerstrasse 16, 53117 Bonn, Germany.
Correspondence to: Roland Schüle1 e-mail: roland.schuele@uniklinik-freiburg.de
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