p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis

Talha Anwar, Caroline Arellano-Garcia, James Ropa, Yu-Chih Chen, Hong Sun Kim, Euisik Yoon, Sierrah Grigsby, Venkatesha Basrur, Alexey I. Nesvizhskii, Andrew Muntean, Maria E. Gonzalez, Kelley M. Kidwell, Zaneta Nikolovska-Coleska and Celina G. Kleer ()
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Talha Anwar: University of Michigan Medical School
Caroline Arellano-Garcia: University of Michigan
James Ropa: University of Michigan Medical School
Yu-Chih Chen: University of Michigan
Hong Sun Kim: University of Michigan Medical School
Euisik Yoon: University of Michigan
Sierrah Grigsby: University of Michigan Medical School
Venkatesha Basrur: University of Michigan Medical School
Alexey I. Nesvizhskii: University of Michigan Medical School
Andrew Muntean: University of Michigan Medical School
Maria E. Gonzalez: University of Michigan Medical School
Kelley M. Kidwell: University of Michigan
Zaneta Nikolovska-Coleska: University of Michigan Medical School
Celina G. Kleer: University of Michigan Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05078-8

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