Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation (original) (raw)

Nature Cell Biology volume 10, pages 53–60 (2008)Cite this article

An Erratum to this article was published on 01 February 2008

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.

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Acknowledgements

We thank C. Beisenherz-Huss, C. Schächtele (ProQinase GmbH, Freiburg) and R. Schneider for providing reagents. We are obliged to T. Günther, H. Greschik, J. M. Müller and S. Naumovitz for discussions. We thank F. Klott for technical assistance. This work was supported by grants from the National Institutes of Health to J.M.G.H., the Deutsche Forschungsgemeinschaft, the Dr Hans Messner Stiftung and Deutsche Krebshilfe to R.S.

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Authors and Affiliations

  1. Universitäts-Frauenklinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, Freiburg, 79106, Germany
    Eric Metzger, Na Yin, Melanie Wissmann, Natalia Kunowska, Kristin Fischer & Roland Schüle
  2. Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, Bonn, 53127, Germany
    Nicolaus Friedrichs & Reinhard Buettner
  3. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA
    Debasis Patnaik & Jonathan M. G. Higgins
  4. Institut de Chimie LC3 – CNRS - UMR 7177, ISIS, 8 allée Gaspard Monge, Strasbourg, 67083, France
    Noelle Potier
  5. Institut für Genetik, Universität Bonn, Römerstrasse 16, Bonn, 53117, Germany
    Karl-Heinz Scheidtmann

Authors

  1. Eric Metzger
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  2. Na Yin
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  3. Melanie Wissmann
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  4. Natalia Kunowska
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  5. Kristin Fischer
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  6. Nicolaus Friedrichs
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  7. Debasis Patnaik
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  8. Jonathan M. G. Higgins
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  9. Noelle Potier
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  10. Karl-Heinz Scheidtmann
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  11. Reinhard Buettner
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  12. Roland Schüle
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Correspondence toRoland Schüle.

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Metzger, E., Yin, N., Wissmann, M. et al. Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation.Nat Cell Biol 10, 53–60 (2008). https://doi.org/10.1038/ncb1668

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