Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Abstract

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: GSKJ4 increases K27 methylation, inhibits K27M glioma cell growth and prevents K27M colony formation.
Figure 2: GSKJ4 treatment shows K27M antitumor activity in vivo.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Wu, G. et al. Nat. Genet. 44, 251–253 (2012).

    Article  CAS  Google Scholar 

  2. Schwartzentruber, J. et al. Nature 482, 226–231 (2012).

    Article  CAS  Google Scholar 

  3. Chan, K.M. et al. Genes Dev. 27, 985–990 (2013).

    Article  CAS  Google Scholar 

  4. Lewis, P.W. et al. Science 340, 857–861 (2013).

    Article  CAS  Google Scholar 

  5. Bender, S. et al. Cancer Cell 24, 660–672 (2013).

    Article  CAS  Google Scholar 

  6. Venneti, S. et al. Brain Pathol. 23, 558–564 (2013).

    Article  CAS  Google Scholar 

  7. Grimm, S.A. & Chamberlain, M.C. Curr. Neurol. Neurosci. Rep. 13, 346 (2013).

    Article  Google Scholar 

  8. Hashizume, R. et al. J. Neurooncol. 110, 305–313 (2012).

    Article  Google Scholar 

  9. Mueller, S. et al. Neuro-oncol. 16, 352–360 (2014).

    Article  CAS  Google Scholar 

  10. Cao, R. et al. Science 298, 1039–1043 (2002).

    Article  CAS  Google Scholar 

  11. Lund, A.H. & van Lohuizen, M. Curr. Opin. Cell Biol. 16, 239–246 (2004).

    Article  CAS  Google Scholar 

  12. Agger, K. et al. Nature 449, 731–734 (2007).

    Article  CAS  Google Scholar 

  13. Kruidenier, L. et al. Nature 488, 404–408 (2012).

    Article  CAS  Google Scholar 

  14. McCabe, M.T. et al. Nature 492, 108–112 (2012).

    Article  CAS  Google Scholar 

  15. Aoki, Y. et al. J. Neurooncol. 108, 29–35 (2012).

    Article  Google Scholar 

  16. Sarkaria, J.N. et al. Clin. Cancer Res. 12, 2264–2271 (2006).

    Article  CAS  Google Scholar 

  17. Bjerke, L. et al. Cancer Discov. 3, 512–519 (2013).

    Article  CAS  Google Scholar 

  18. Langmead, B. & Salzberg, S.L. Nat. Methods 9, 357–359 (2012).

    Article  CAS  Google Scholar 

  19. Kharchenko, P.V., Tolstorukov, M.Y. & Park, P.J. Nat. Biotechnol. 26, 1351–1359 (2008).

    Article  CAS  Google Scholar 

  20. Zhu, L.J. et al. BMC Bioinformatics 11, 237 (2010).

    Article  Google Scholar 

Download references

Acknowledgements

Supported by US National Institutes of Health (NIH) Brain Tumor SPORE grant CA97257 (R.H., C.D.J.), the Pediatric Brain Tumor Foundation (R.H., N.G., C.D.J.), the Matthew Larson Foundation (R.H.), the Bear Necessities Pediatric Cancer Foundation (R.H.) and Rally Foundation (R.H.), American Cancer Society IRG-97-150-13 (R.H.), NIH CA157489 (Z.Z.), the Childhood Brain Tumor Foundation (C.P.), the Voices Against Brain Tumor Foundation (C.P.) and NIH CA164746 (C.P.).

Author information

Authors and Affiliations

Authors

Contributions

R.H. designed and conducted all of the experiments and wrote the manuscript. N.A. performed bioinformatics analysis for the data from gene expression and ChIP-seq. Y.I. performed the in vitro studies and provided valuable discussion. R.L. performed the cell cycle analysis, flow cytometry analysis and quantitative RT-PCR. H.G., X.C. and D.F. performed the ChIP-seq experiments. X.H. provided valuable discussion and intellectual input. M.W.T. performed the in vitro studies. V.N. performed microarray analysis. D.S. provided valuable material and intellectual input. S.M. provided clinical information and conceptual advice. P.L.P. supervised microarray analysis and provided valuable discussion and intellectual input. Z.Z. supervised ChIP-seq experiments and provided valuable discussion. C.P. supervised the in vitro experiments and provided valuable discussion and intellectual input. N.G. provided clinical information and supervised the projects. T.A.W. provided valuable discussion and intellectual input and edited the manuscript. C.D.J. supervised the projects, provided valuable discussion and conceptual advice and edited the manuscript.

Corresponding author

Correspondence to Rintaro Hashizume.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 1–3 (PDF 7557 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashizume, R., Andor, N., Ihara, Y. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20, 1394–1396 (2014). https://doi.org/10.1038/nm.3716

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3716

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing