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Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

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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Figure 1: PRK1 controls androgen receptor (AR)-dependent gene expression and associates with chromatin.
Figure 2: PRK1 phosphorylates histone H3 at threonine 11 (H3T11).
Figure 3: PRK1 controls modifications of histone H3 and androgen receptor-dependent gene expression.
Figure 4: PRK1 controls transition to the initiation complex and accelerates demethylation by JMJD2C.
Figure 5: PRK1 and H3T11ph levels positively correlate with the malignancy of prostate cancer and control proliferation of tumour cells.

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References

  1. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Phatnani, H. P. & Greenleaf, A. L. Phosphorylation and functions of the RNA polymerase II CTD. Genes Dev. 20, 2922–2936 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Wissmann, M. et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nature Cell Biol. 9, 347–353 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Kang, Z., Pirskanen, A., Janne, O. A. & Palvimo, J. J. Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J. Biol. Chem. 277, 48366–48371 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Metzger, E. et al. A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer. EMBO J. 22, 270–280 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Preuss U., Landsberg G. & Scheidtmann K. H. Novel mitosis-specific phosphorylation of histone H3 at Thr11 mediated by Dlk/ZIP kinase. Nucleic Acids Res. 31, 878–885 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tachibana M., Sugimoto K., Fukushima T. & Shinkai Y. SET domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Ogawa H., Ishiguro K., Gaubatz S., Livingston D. M. & Nakatani Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296, 1132–1136 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Baek S. H. et al. Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells. Proc. Natl Acad. Sci. USA 103, 3100–3105 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kononen J. et al. Tissue microarrays for high-throughput molecular profiling of tumour specimens. Nature Med. 4, 844–847 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Kahl, P. et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 66, 11341–11347 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Ng S. S. et al. Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 448, 87–91 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Zippo A., De Robertis A., Serafini R. & Oliviero S. PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation. Nature Cell Biol. 9, 932–944 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Garcia-Bassets I. et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128, 505–518 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dai, J., Sultan, S., Taylor, S. S. & Higgins, J. M. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 19, 472–488 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shang, Y., Myers, M. & Brown, M. Formation of the androgen receptor transcription complex. Mol. Cell 9, 601–610 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Wiznerowicz, M. & Trono, D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J. Virol. 77, 8957–8961 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dong, L. Q. et al. Phosphorylation of protein kinase N by phosphoinositide-dependent protein kinase-1 mediates insulin signals to the actin cytoskeleton. Proc. Natl Acad. Sci. USA 97, 5089–5094 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. O'Neill, T. E., Roberge, M. & Bradbury, E. M. Nucleosome arrays inhibit both initiation and elongation of transcripts by bacteriophage T7 RNA polymerase. J. Mol. Biol. 223, 67–78 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Schroder, F. H. et al. The TNM classification of prostate cancer. Prostate Suppl. 4, 129–138 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Hsing, A. W., Tsao L. & Devesa S. S. International trends and patterns of prostate cancer incidence and mortality. Int. J. Cancer 85, 60–67 (2000).

    Article  CAS  PubMed  Google Scholar 

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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

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Correspondence to Roland 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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