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, Celina G. Kleer

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Article number2801
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Bibliographical note

Funding Information:
We thank members of the Kleer lab for discussions during the execution of this project. We thank the lab of Dr. Pier Lorenzo Puri for myc-EZH2 and T367A-EZH2 vectors. This work was supported by the National institutes of Health (NIH) grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), R25GM086262 (PREP program, C.A.-G.), R01GM094231 (A.I.N.), T32CA140044 (J.R.), the University of Michigan Rogel Cancer Center support grant P30CA046592, the Karlene Kulp Fund Judy & Ken Robinson Fund (C.G.K.) and the Department of Defense award W81XWH-15-1-0019 (C.G.K. and Z.N.-C.).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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