Tumors with SWI/SNF subunit mutations depend on both catalytic and noncatalytic activity of EZH2.
Major finding: Tumors with SWI/SNF subunit mutations depend on both catalytic and noncatalytic activity of EZH2.
Concept: EZH2 dependence is a shared feature of cancer cells harboring inactivating mutations in SWI/SNF subunits.
Impact: EZH2 enzymatic inhibitors may not be sufficient to disrupt the oncogenic effects of EZH2.
Components of the SWI/SNF chromatin remodeling complex are mutated in approximately 20% of human cancers. An antagonistic relationship has been reported between the SWI/SNF subunit SMARCB1 (also known as SNF5) and EZH2, the catalytic methyltransferase subunit of polycomb repressive complex 2 (PRC2), wherein SMARCB1-deficient tumors are genetically dependent on unrestrained EZH2 function. Kim and colleagues found that most cancer cell lines with inactivating mutations in genes encoding other SWI/SNF subunits frequently mutated in cancer, such as ARID1A, SMARCA4 (BRG1), and PBRM1, were also dependent on EZH2 and selectively sensitive to EZH2 depletion. The SWI/SNF-mutant cell lines that did not require EZH2 were enriched for activating RAS pathway mutations, suggesting that RAS mutations reduce the dependence of SWI/SNF-mutant tumors on EZH2. Inhibitors targeting EZH2 histone methyltransferase activity are in clinical trials; however, it is unclear if EZH2 catalytic activity is required for the oncogenic effects of EZH2 in SWI/SNF-mutant cancers. GSK126, an enzymatic inhibitor of EZH2 histone methyltransferase activity, reduced H3K27 trimethylation in all cells, but although all SWI/SNF-mutant cells were sensitive to EZH2 knockdown in vitro and in vivo, only some were sensitive to GSK126. Surprisingly, EZH2 mutants lacking methyltransferase activity were largely able to rescue the effects of EZH2 knockdown, suggesting that the effects of EZH2 depletion on SWI/SNF-mutant cells are not entirely due to loss of EZH2 enzymatic activity. SAH-EZH2, a stapled peptide that blocks H3K27 trimethylation by destabilizing the PRC2 complex and inducing EZH2 degradation, inhibited the growth of SWI/SNF-mutant cancer cells, including those that were insensitive to GSK126. Together, these data suggest that a methyltransferase-independent function of EZH2 plays a predominant role in supporting the growth and proliferation of SWI/SNF-mutant cells. Inhibiting the methyltransferase activity of EZH2 may therefore not be sufficient to fully block its oncogenic effects.
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