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

Author

Listed:
  • Talha Anwar

    (University of Michigan Medical School
    University of Michigan
    University of Michigan
    University of Michigan)

  • Caroline Arellano-Garcia

    (University of Michigan)

  • James Ropa

    (University of Michigan Medical School
    University of Michigan)

  • Yu-Chih Chen

    (University of Michigan
    University of Michigan)

  • Hong Sun Kim

    (University of Michigan Medical School
    University of Michigan)

  • Euisik Yoon

    (University of Michigan
    University of Michigan)

  • Sierrah Grigsby

    (University of Michigan Medical School
    University of Michigan)

  • 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
    University of Michigan)

  • Kelley M. Kidwell

    (University of Michigan)

  • Zaneta Nikolovska-Coleska

    (University of Michigan Medical School)

  • Celina G. Kleer

    (University of Michigan Medical School
    University of Michigan)

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.

Suggested Citation

  • 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 & Kel, 2018. "p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05078-8
    DOI: 10.1038/s41467-018-05078-8
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    Cited by:

    1. Nikhil B. Ghate & Sungmin Kim & Yonghwan Shin & Jinman Kim & Michael Doche & Scott Valena & Alan Situ & Sangnam Kim & Suhn K. Rhie & Heinz-Josef Lenz & Tobias S. Ulmer & Shannon M. Mumenthaler & Wooji, 2023. "Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Ayushi Verma & Akhilesh Singh & Manish Pratap Singh & Mushtaq Ahmad Nengroo & Krishan Kumar Saini & Saumya Ranjan Satrusal & Muqtada Ali Khan & Priyank Chaturvedi & Abhipsa Sinha & Sanjeev Meena & Anu, 2022. "EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    3. Brajendra K. Tripathi & Meghan F. Anderman & Disha Bhargava & Luciarita Boccuzzi & Xiaolan Qian & Dunrui Wang & Marian E. Durkin & Alex G. Papageorge & Fernando J. Miguel & Katerina Politi & Kylie J. , 2021. "Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Pauliina M. Munne & Lahja Martikainen & Iiris Räty & Kia Bertula & Nonappa & Janika Ruuska & Hanna Ala-Hongisto & Aino Peura & Babette Hollmann & Lilya Euro & Kerim Yavuz & Linda Patrikainen & Maria S, 2021. "Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    5. Julie Rondeaux & Déborah Groussard & Sylvanie Renet & Virginie Tardif & Anaïs Dumesnil & Alphonse Chu & Léa Maria & Théo Lemarcis & Manon Valet & Jean-Paul Henry & Zina Badji & Claire Vézier & Delphin, 2023. "Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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