Letter | Published:

Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression

Nature Cell Biology volume 9, pages 347353 (2007) | Download Citation



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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & The language of covalent histone modifications. Nature 403, 41–45 (2000).

  2. 2.

    et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

  3. 3.

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

  4. 4.

    et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 435, 811–816 (2005).

  5. 5.

    et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

  6. 6.

    et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).

  7. 7.

    et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).

  8. 8.

    et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).

  9. 9.

    , & Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20, 1405–1428 (2006).

  10. 10.

    et al. JHDM2A, a JmjC-containing H3K9 demethylase facilitates Transcription activation by androgen receptor. Cell 125, 483–495 (2006).

  11. 11.

    , & Methylation: lost in hydroxylation? EMBO Rep. 6, 315–320 (2005).

  12. 12.

    et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).

  13. 13.

    et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312–316 (2006).

  14. 14.

    & Histone lysine demethylases and their impact on epigenetics. Cell 125, 213–217 (2006).

  15. 15.

    , , & Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J. Biol. Chem. 277, 48366–48371 (2002).

  16. 16.

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

  17. 17.

    et al. Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein. J. Biol. Chem. 280, 28507–28518 (2005).

  18. 18.

    et al. The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus. EMBO J. 21, 736–748 (2002).

  19. 19.

    et al. FHL2, a novel tissue-specific coactivator of the androgen receptor. EMBO J. 19, 359–369 (2000).

  20. 20.

    , & Formation of the androgen receptor transcription complex. Mol. Cell 9, 601–610 (2002).

  21. 21.

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

  22. 22.

    , & Nucleosome arrays inhibit both initiation and elongation of transcripts by bacteriophage T7 RNA polymerase. J. Mol. Biol. 223, 67–78 (1992).

  23. 23.

    et al. A generic protein purification method for protein complex characterization and proteome exploration. Nature Biotechnol. 17, 1030–1032 (1999).

Download references


We thank S. Gray for generously providing reagents. We thank K. Fischer, L. Walz, F. Klott and S. Vomstein for excellent technical assistance. We are obliged to M. Hoffmann and A. Schwentek from the sequencing core facility. We thank M. Follo for help with editing the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 747/P2, Schu 688/7-1, and Schu 688/9-1), the Dr. Hans Messner-Stiftung, and the Deutsche Krebshilfe (10-2019-Bu I) to R.S.

Author information


  1. Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.

    • Melanie Wissmann
    • , Na Yin
    • , Judith M. Müller
    • , Holger Greschik
    • , Thomas Günther
    • , Eric Metzger
    •  & Roland Schüle
  2. Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr. Bohrgasse 7, 1030 Vienna, Austria.

    • Barna D. Fodor
    •  & Thomas Jenuwein
  3. Max-Planck-Institut für Immunbiologie, Stübeweg 51, 79108 Freiburg, Germany.

    • Christine Vogler
    •  & Robert Schneider
  4. Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.

    • Reinhard Buettner


  1. Search for Melanie Wissmann in:

  2. Search for Na Yin in:

  3. Search for Judith M. Müller in:

  4. Search for Holger Greschik in:

  5. Search for Barna D. Fodor in:

  6. Search for Thomas Jenuwein in:

  7. Search for Christine Vogler in:

  8. Search for Robert Schneider in:

  9. Search for Thomas Günther in:

  10. Search for Reinhard Buettner in:

  11. Search for Eric Metzger in:

  12. Search for Roland Schüle in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Roland Schüle.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary figures S1, S2, S3, S4 and S5

About this article

Publication history






Further reading