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SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2
Open accessAbstract
Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.
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Metadata
- Authors
- Kim, K. H., Kim, W., Howard, T. P., Vazquez, F., Tsherniak, A., Wu, J. N., Wang, W., Haswell, J. R., Walensky, L. D., Hahn, W. C., Orkin, S. H., & Roberts, C. W. M.
- Venue
- Nature Medicine
- Published
- 2015-11-09
- Volume
- 21
- Issue
- 12
- Pages
- 1491-1496
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2190015925
- Cited by
- 406
- References
- 42
- FWCI
- 17.88
- Type
- journal article
- Language
- en
- Open access
- green
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