SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.
Authors | |
Keywords | |
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. |
Year of Publication | 2015
|
Journal | Nat Med
|
Volume | 21
|
Issue | 12
|
Pages | 1491-6
|
Date Published | 2015 Dec
|
ISSN | 1546-170X
|
URL | |
DOI | 10.1038/nm.3968
|
PubMed ID | 26552009
|
PubMed Central ID | PMC4886303
|
Links | |
Grant list | U01CA176058 / CA / NCI NIH HHS / United States
R01CA172152 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 CA113794 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
R01 CA172152 / CA / NCI NIH HHS / United States
R01CA113794 / CA / NCI NIH HHS / United States
|