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 language | English (US) |
---|---|
Pages (from-to) | 2907-2917 |
Number of pages | 11 |
Journal | Cell reports |
Volume | 18 |
Issue number | 12 |
DOIs | |
State | Published - Mar 21 2017 |
Funding
We thank all members of the Roussel/Sherr laboratory for helpful discussions and comments during the course of these experiments. We are indebted to the Core Flow Cytometry and Cell Sorting Shared Resource facility; the Pathology Core; and Melissa Johnson, Shantel Brown, and Allison Weaver from the Small Animal Imaging Core for cranial implants. We thank Jose Grenet for making high-titer retroviruses, and Dana Farmer and Frederique Zindy for tumor cell purification and fixation of cells for ChIP-seq analysis. This work was funded in part by the NIH grants CA-096832 and CA-21765 to M.F.R., Sununu Endowed Fellowship to B.T.V., and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital. C.J.S. is an investigator of the Howard Hughes Medical Institute.
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
- General Biochemistry, Genetics and Molecular Biology