Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma
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
Affiliations
BaoHan T. Vo
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Chunliang Li
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Marc A. Morgan
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA
Ilan Theurillat
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
David Finkelstein
Department of Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Shaela Wright
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Judith Hyle
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Stephanie M.C. Smith
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Yiping Fan
Department of Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Yong-Dong Wang
Department of Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Gang Wu
Department of Computational Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Brent A. Orr
Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Paul A. Northcott
Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Ali Shilatifard
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA
Charles J. Sherr
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Martine F. Roussel
Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
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.
