Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma

Bao Han T. Vo, Chunliang Li, Marc A. Morgan, Ilan Theurillat, David Finkelstein, Shaela Wright, Judith Hyle, Stephanie M.C. Smith, Yiping Fan, Yong Dong Wang, Gang Wu, Brent A. Orr, Paul A. Northcott, Ali Shilatifard, Charles J. Sherr, Martine F. Roussel*

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The most aggressive of four medulloblastoma (MB) subgroups are cMyc-driven group 3 (G3) tumors, some of which overexpress EZH2, the histone H3K27 mono-, di-, and trimethylase of polycomb-repressive complex 2. Ezh2 has a context-dependent role in different cancers as an oncogene or tumor suppressor and retards tumor progression in a mouse model of G3 MB. Engineered deletions of Ezh2 in G3 MBs by gene editing nucleases accelerated tumorigenesis, whereas Ezh2 re-expression reversed attendant histone modifications and slowed tumor progression. Candidate oncogenic drivers suppressed by Ezh2 included Gfi1, a proto-oncogene frequently activated in human G3 MBs. Gfi1 disruption antagonized the tumor-promoting effects of Ezh2 loss; conversely, Gfi1 overexpression collaborated with Myc to bypass effects of Trp53 inactivation in driving MB progression in primary cerebellar neuronal progenitors. Although negative regulation of Gfi1 by Ezh2 may restrain MB development, Gfi1 activation can bypass these effects.

Original languageEnglish (US)
Pages (from-to)2907-2917
Number of pages11
JournalCell reports
Volume18
Issue number12
DOIs
StatePublished - Mar 21 2017

Keywords

  • EZH2
  • GFI1
  • Hox genes
  • MYC
  • PRC2
  • SUZ12
  • enhancer of zeste homology 2
  • epigenetic repression
  • group 3 medulloblastoma
  • growth factor independent 1
  • histone H3 modification
  • polycomb-repressive complex 2
  • suppressor of zeste 12 homolog

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Vo, B. H. T., Li, C., Morgan, M. A., Theurillat, I., Finkelstein, D., Wright, S., Hyle, J., Smith, S. M. C., Fan, Y., Wang, Y. D., Wu, G., Orr, B. A., Northcott, P. A., Shilatifard, A., Sherr, C. J., & Roussel, M. F. (2017). Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma. Cell reports, 18(12), 2907-2917. https://doi.org/10.1016/j.celrep.2017.02.073