Targeted Disruption of the EZH2/EED Complex Inhibits EZH2-dependent Cancer
Open/View files
Date
2013
Author(s)
Neff, Tobias
The Harvard community has made this article openly available. Please share how this access benefits you.
Citation
Kim, Woojin, Gregory H. Bird, Tobias Neff, Guoji Guo, Marc A. Kerenyi, Loren D. Walensky, and Stuart H. Orkin. 2013. “Targeted Disruption of the EZH2/EED Complex Inhibits EZH2-dependent Cancer.” Nature chemical biology 9 (10): 643-650. doi:10.1038/nchembio.1331. http://dx.doi.org/10.1038/nchembio.1331.
Abstract
Enhancer of zeste homolog2 (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 (SUZ12), 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 alpha-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.
Other Available Sources
Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material (LAA), as set forth at Terms of Service
Collection