Inactivation of Ezh2 Upregulates Gfi1 and Drives Aggressive Myc-Driven Group 3 Medulloblastoma.
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.
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
BaoHan T
BT
Vo
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Chunliang
C
Li
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
Marc A
MA
Morgan
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Institut Pasteur, 25-28, rue du Docteur-Roux, 75724 Paris Cedex 15, France.
Ilan
I
Theurillat
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
David
D
Finkelstein
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Howard Hughes Medical Institute, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Shaela
S
Wright
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Howard Hughes Medical Institute, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Judith
J
Hyle
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Stephanie M C
SMC
Smith
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Yiping
Y
Fan
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Yong-Dong
YD
Wang
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Gang
G
Wu
Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Brent A
BA
Orr
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Paul A
PA
Northcott
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
Ali
A
Shilatifard
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Howard Hughes Medical Institute, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Charles J
CJ
Sherr
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: martine.roussel@stjude.org.
Martine F
MF
Roussel
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D009857:Oncogenes; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C430461:SUZ12 protein, human; D014157:Transcription Factors; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
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