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SWI/SNF nucleosome remodellers and cancer

Key Points

  • Specific inactivating mutations in subunits of SWI/SNF chromatin remodelling complexes, including the SNF5 (also known as SMARCB1, INI1 and BAF47), ARID1A (also known as BAF250A and SMARCF1), BAF180 (also known as PBRM1) and BRM/SWI2-related gene 1 (BRG1; also known as SMARCA4) subunits, occur at a high frequency in several types of cancer.

  • Genetically engineered mice carrying mutations in Snf5 and Brg1 have established that at least some SWI/SNF subunits have bona fide tumour suppressor activity.

  • SWI/SNF complexes regulate gene expression by using the energy of ATP to remodel chromatin.

  • A central function of SWI/SNF complexes is the coordinated regulation of gene expression programmes. These complexes have essential roles during lineage specification and in the maintenance of stem cell pluripotency.

  • Emerging evidence has identified key pathways that contribute to tumorigenesis following perturbation of SWI/SNF complexes.

  • Collectively, enzymes that modify chromatin structure are emerging as key regulators of tumorigenesis. As epigenetic alterations are potentially reversible, unlike DNA mutations, the targeted inhibition of chromatin-modifying enzymes may have important therapeutic implications for cancer.

Abstract

SWI/SNF chromatin remodelling complexes use the energy of ATP hydrolysis to remodel nucleosomes and to modulate transcription. Growing evidence indicates that these complexes have a widespread role in tumour suppression, as inactivating mutations in several SWI/SNF subunits have recently been identified at a high frequency in a variety of cancers. However, the mechanisms by which mutations in these complexes drive tumorigenesis are unclear. In this Review we discuss the contributions of SWI/SNF mutations to cancer formation, examine their normal functions and discuss opportunities for novel therapeutic interventions for SWI/SNF-mutant cancers.

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Figure 1: SWI/SNF chromatin remodelling complexes.
Figure 2: SWI/SNF complexes facilitate factor binding.
Figure 3: Target pathways implicated in the tumour suppressor activity of SWI/SNF complexes.

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Acknowledgements

The authors especially thank E. McKenna, L. Mora-Blanco and S. Jhaveri-Schneider for critical reading of the manuscript and for helpful discussions.

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Correspondence to Charles W. M. Roberts.

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C.W.M.R. is a recipient of a Dana-Farber Cancer Institute/Novartis Drug Discovery Grant and receives consulting fees from the Novartis Institute of Biomedical Research. B.G.W. declares no competing financial interests.

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Polycomb group (PcG) proteins

These proteins covalently modify histones and have roles in regulating gene expression during essential cell fate decisions. They have been divided into families based on biochemical purifications into two distinct complexes: polycomb repressive complex 1 (PRC1) and PRC2. The catalytic subunit of the PRC2 complexes EZH2 mediates trimethylation of histone H3 at lysine 27, which in turn is a histone binding site for PRC1 complexes, cooperatively leading to the formation of a repressive chromatin environment.

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Wilson, B., Roberts, C. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 11, 481–492 (2011). https://doi.org/10.1038/nrc3068

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