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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

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


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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