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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.

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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.

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References

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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.).

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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.

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Correspondence to Rintaro Hashizume.

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The authors declare no competing financial interests.

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

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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

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