Targeted Disruption of the EZH2/EED Complex Inhibits EZH2-dependent Cancer
Woojin Kim,Gregory H. Bird,Tobias Neff,Guoji Guo,Guoji Guo,Marc A. Kerenyi,Marc A. Kerenyi,Loren D. Walensky,Stuart H. Orkin +8 more
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TLDR
By dissociating the EZH2/EED complex, this work pharmacologically modulates an epigenetic “writer” and suppress PRC2-dependent cancer cell growth.Abstract:
Enhancer of zeste homolog 2 (EZH2) is the histone lysine N-methyltransferase component of the Polycomb repressive complex 2 (PRC2), which, in conjunction with embryonic ectoderm development (EED) and suppressor of zeste 12 homolog, regulates cell lineage determination and homeostasis. Enzymatic hyperactivity has been linked to aberrant repression of tumor suppressor genes in diverse cancers. Here, we report the development of stabilized α-helix of EZH2 (SAH-EZH2) peptides that selectively inhibit H3 Lys27 trimethylation by dose-responsively disrupting the EZH2-EED complex and reducing EZH2 protein levels, a mechanism distinct from that reported for small-molecule EZH2 inhibitors targeting the enzyme catalytic domain. MLL-AF9 leukemia cells, which are dependent on PRC2, undergo growth arrest and monocyte-macrophage differentiation upon treatment with SAH-EZH2, consistent with observed changes in expression of PRC2-regulated, lineage-specific marker genes. Thus, by dissociating the EZH2-EED complex, we pharmacologically modulate an epigenetic 'writer' and suppress PRC2-dependent cancer cell growth.read more
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Targeting EZH2 in cancer
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Epigenetic balance of gene expression by Polycomb and COMPASS families.
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TL;DR: The balance between the prototypic chromatin modifiers Polycomb and COMPASS complexes and their role in gene regulation and normal development is reviewed, with evidence supporting a role for these complexes in tumor progression.
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