Abstract
Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology
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Breast Neoplasms / therapy
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Carcinoma, Ductal, Breast / genetics*
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Carcinoma, Ductal, Breast / mortality
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Carcinoma, Ductal, Breast / secondary
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Carcinoma, Ductal, Breast / therapy
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Cell Line, Tumor
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Cell Movement
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Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
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Enhancer of Zeste Homolog 2 Protein / genetics*
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Enhancer of Zeste Homolog 2 Protein / metabolism
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Female
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Gene Expression Regulation, Neoplastic*
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Heterografts
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Histones / genetics
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Histones / metabolism
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Humans
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Lung Neoplasms / genetics*
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Lung Neoplasms / mortality
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Lung Neoplasms / secondary
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Lung Neoplasms / therapy
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Mice
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Mice, SCID
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Phosphorylation
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Survival Analysis
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Threonine
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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ESR1 protein, human
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Estrogen Receptor alpha
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Histones
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RNA, Small Interfering
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Threonine
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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p38 Mitogen-Activated Protein Kinases