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Nat Med. 2015 Dec;21(12):1491-6. doi: 10.1038/nm.3968. Epub 2015 Nov 9.

SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.

Kim KH1,2,3, Kim W1,2,3, Howard TP1,2,3, Vazquez F4, Tsherniak A4, Wu JN1,2,3,4, Wang W1,2,3, Haswell JR1,2,3, Walensky LD1,2,3, Hahn WC4,5,6, Orkin SH1,2,3,7, Roberts CW1,2,3,4,7.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
3
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
4
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
6
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Howard Hughes Medical Institute, Boston, Massachusetts, USA.

Abstract

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.

PMID:
26552009
PMCID:
PMC4886303
DOI:
10.1038/nm.3968
[Indexed for MEDLINE]
Free PMC Article
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