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

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.

• 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
• Journal: Nature medicine (Nat Med) Vol. 21 Issue 12 Pg. 1491-6 (Dec 2015) ISSN: 1546-170X [Electronic] United States
• PMID: 26552009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromosomal Proteins, Non-Histone
• Enzyme Inhibitors
• GSK-2816126
• Indoles
• Pyridones
• RNA, Small Interfering
• SWI-SNF-B chromatin-remodeling complex
• Transcription Factors
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2

Topics

• Acetylation (drug effects)
• Animals
• Catalysis (drug effects)
• Cell Line, Tumor
• Chromosomal Proteins, Non-Histone (genetics)
• Drug Resistance, Neoplasm (drug effects)
• Enhancer of Zeste Homolog 2 Protein
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Indoles (pharmacology)
• Methylation (drug effects)
• Mice, Nude
• Mutation (genetics)
• Neoplasms (genetics)
• Phosphorylation (drug effects)
• Polycomb Repressive Complex 2 (metabolism)
• Pyridones (pharmacology)
• RNA, Small Interfering (metabolism)
• Transcription Factors (genetics)
• Xenograft Model Antitumor Assays