SWI/SNF-mutant Cancers Depend on Catalytic and Non-catalytic Activity of EZH2

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2015 Nov 10

PMID 26552009

Citations 222

Authors

Kimberly H Kim

Woojin Kim

Thomas P Howard

Francisca Vazquez

Aviad Tsherniak

Jennifer N Wu

Weishan Wang

Jeffrey R Haswell

Loren D Walensky

William C Hahn

Stuart H Orkin

Charles W M Roberts

Affiliations

Soon will be listed here.

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.

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