TY - JOUR
T1 - Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation
AU - Wilson, Boris G.
AU - Wang, Xi
AU - Shen, Xiaohua
AU - McKenna, Elizabeth S.
AU - Lemieux, Madeleine E.
AU - Cho, Yoon Jae
AU - Koellhoffer, Edward C.
AU - Pomeroy, Scott L.
AU - Orkin, Stuart H.
AU - Roberts, Charles W.M.
N1 - Funding Information:
Grant support was from the American Cancer Society New England Division-SpinOdyssey Postdoctoral Fellowship #PF-07-261-01-DDC from the American Cancer Society and the Ruth L. Kirschstein National Research Service Award Fellowship 1 F32 CA130312-01A1 from the National Cancer Institute (B.G.W.). This work was supported in part by a U01 NCI Mouse Models of Cancer Consortium Award (S.H.O. and C.W.M.R.) and a PHS award R01CA113794 (C.W.M.R.). C.W.M.R. is a recipient of an Innovative Research Grant from Stand Up 2 Cancer. The Garrett B. Smith Foundation, the Claudia Adams Barr Foundation, the Sarcoma Foundation of America (C.W.M.R.), and a R01 CA109467 research project grant (S.L.P.) provided additional support. S.H.O. is an Investigator of the HHMI. We thank Jen Perry for helpful discussions and permission to cite unpublished data. We also thank Pablo Tamayo for help with cross-platform analysis of microarray data, Pengcheng Zhou for isolation of murine cerebellum cells, and David James for the BT16 cell line.
PY - 2010/10/19
Y1 - 2010/10/19
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2010.09.006
DO - 10.1016/j.ccr.2010.09.006
M3 - Article
C2 - 20951942
AN - SCOPUS:77957955244
SN - 1535-6108
VL - 18
SP - 316
EP - 328
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -