Epigenetic antagonism between Polycomb and SWI/SNF complexes during oncogenic transformation

By B. Wilson, Xi Wang, Xiaohua Shen, Elizabeth S. McKenna, M. Lemieux, Yoon-Jae Cho, E. Koellhoffer, S. Pomeroy, Stuart H. Orkin, C. Roberts. Cancer Cell, 2010

610 citations recorded by the source corpus.

Summary 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.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/e1982f6b1349e947badbde1e3996acc3fa6ba1c0

How researchers see this paper

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In Molecular Biology

1. Peter A. Jones
2. S. Baylin
3. Zuguang Gu
4. J. Audia
5. R. Campbell
6. V. Richon
7. R. Pollock
8. Jan O. Korbel

In Pathology and Forensic Medicine

1. Peter A. Jones
2. S. Baylin

Citations in the corpus

• A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “A recent mouse knockout model forthis mutation has shown a tumour phenotype that seems to be entirely dependent on the activity of the PcG pathway for downstream effect”
• The whole-genome landscape of medulloblastoma subtypes (2017, positive): “Given the epigenetic antagonism known to exist between SWI/SNF and the PRC2 polycomb repressive complex 26 trials (NCT02601937) and based on our findings here, could represent a rational targeted therapy for treating WNT MB.”
• Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2 (2013, background): “SMARCB1-conditional inactivation in T cells leads to fully penetrant T-cell lymphomas at a median age of onset of 11 wk (17).”
• Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics (2015, background): “BAF complexes in the mutant cells are unable to remove Polycomb complexes and their histone modification, H3K27Me3, from the Ink4a (Cdkn2a) locus, which normally suppresses proliferation (69).”
• SWI/SNF nucleosome remodellers and cancer (2011, background): “Inactivation of Snf5 in primary embryonic fibroblasts also leads to the upregulation of stem cell-associated signatures, with enrichment of these signatures in SNF5-deficient RTs, which is a poorly differentiated cance”
• Histone Modifications and Cancer. (2016, background): “SWI/SNF, in fact, critically depends on EZH2 activity, as shown in cell lines and mouse models in which inactivation of EZH2 blocked tumor formation driven by SNF5 loss (Wilson et al. 2010).”