A peptide that prevents EZH2 from binding EED inhibits growth of EZH2-dependent cancer cells.

  • Major finding: A peptide that prevents EZH2 from binding EED inhibits growth of EZH2-dependent cancer cells.

  • Concept: Stabilized alpha helix of EZH2 (SAH-EZH2) is a stapled peptide that mimics the EED-binding domain.

  • Impact: Preventing PRC2 complex assembly is an alternative strategy for H3K27 methyltransferase inhibition.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2), which catalyzes histone H3 lysine 27 (H3K27) trimethylation as part of Polycomb repressive complex 2 (PRC2), is an attractive therapeutic target because its upregulation or mutational activation promotes the development and maintenance of several cancer types. Most efforts to develop EZH2 inhibitors have focused on small molecules that bind the EZH2 active site, an approach that fails to inhibit alternative PRC2 complexes containing the EZH2 homolog EZH1. Kim and colleagues developed a strategy to inhibit PRC2 enzymatic activity by blocking the interaction between EZH2 and another PRC2 subunit, embryonic ectoderm development (EED). Hydrocarbon “stapling” was used to create a stabilized alpha helix (SAH) that mimicked the alpha-helical EED-binding domain of EZH2, which shares 86% amino acid identity with EZH1. This stapled peptide, SAH-EZH2, was cell permeable, disrupted interactions between EED and both EZH2 and EZH1, and selectively inhibited H3K27 methylation in a dose-dependent manner. Importantly, SAH-EZH2 treatment inhibited proliferation and induced differentiation in MLLAF9-expressing murine leukemia cells, which are dependent on EZH2 and PRC2 activity for growth, while sparing nontumorigenic cells. SAH-EZH2 also impaired proliferation in EZH2-overexpressing human breast and prostate cancer cell lines and EZH2-mutant B-cell lymphoma cells. Although a small-molecule catalytic site EZH2 inhibitor more potently inhibited H3K27 methylation in vitro, SAH-EZH2 had stronger and more specific effects on cancer cell viability and reduced EZH2 stability in addition to inhibiting its activity. Combined use of the two agents led to synergistic inhibition of EZH2-dependent cancer cell growth, providing further evidence for distinct and complementary mechanisms of action. These findings thus establish the feasibility of targeting EZH2 through disruption of PRC2 complex formation and provide a framework for targeting other epigenetic modifiers that are deregulated in human cancers.

Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD, et al. Targeted disruption of the EZH2–EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 2013;9:643–50.

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