Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation.
Epigenetic alterations have been increasingly implicated in oncogenesis. Analysis of Drosophila mutants suggests that Polycomb and SWI/SNF complexes can serve antagonistic developmental roles. However, the relevance of this relationship to human disease is unclear. Here, we have investigated functional relationships between these epigenetic regulators in oncogenic transformation. Mechanistically, we show that loss of the SNF5 tumor suppressor leads to elevated expression of the Polycomb gene EZH2 and that Polycomb targets are broadly H3K27-trimethylated and repressed in SNF5-deficient fibroblasts and cancers. Further, we show antagonism between SNF5 and EZH2 in the regulation of stem cell-associated programs and that Snf5 loss activates those programs. Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston, Harvard Medical School, MA 02115, USA.
Boris G
BG
Wilson
Xi
X
Wang
Xiaohua
X
Shen
Elizabeth S
ES
McKenna
Madeleine E
ME
Lemieux
Yoon-Jae
YJ
Cho
Edward C
EC
Koellhoffer
Scott L
SL
Pomeroy
Stuart H
SH
Orkin
Charles W M
CW
Roberts
D000818:Animals; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008957:Models, Genetic; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D000071796:SMARCB1 Protein; D013234:Stem Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
D002868:Chromosomal Proteins, Non-Histone; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine