Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation

SummaryEpigenetic 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.

► The SNF5 tumor suppressor and EZH2 antagonistically regulate gene expression
► Polycomb-regulated genes are broadly repressed in SNF5-deficient tumors
► SNF5 and EZH2 modulate stem cell-associated programs, and SNF5 loss activates them
► Ezh2 is essential for tumor formation caused by Snf5 inactivation in vivo