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

Publication date: 21 March 2017
Source:Cell Reports, Volume 18, Issue 12
Author(s): BaoHan 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
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.

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Teaser

Vo et al. show that inactivation of Ezh2 by gene editing accelerated tumor initiation and progression in a mouse model of cMyc-driven group 3 medulloblastoma. Loss of Ezh2 derepressed expression of Gfi1, an oncogenic driver that cooperates with Myc to promote medulloblastoma development.


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