EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression

Maria E Gonzalez; Giuseppina Daniela Naimo; Talha Anwar; Alessandro Paolì; Shilpa R Tekula; Suny Kim; Natasha Medhora; Shoshana A Leflein; Jacob Itkin; Raymond Trievel; Kelley M Kidwell; Yu-Chih Chen; Loredana Mauro; Euisik Yoon; Sebastiano Andò; Celina G Kleer

doi:10.1016/j.isci.2022.104827

EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression

iScience. 2022 Aug 2;25(8):104827. doi: 10.1016/j.isci.2022.104827. eCollection 2022 Aug 19.

Authors

Maria E Gonzalez^{1

2}, Giuseppina Daniela Naimo^{1

3}, Talha Anwar⁴, Alessandro Paolì^{1

3}, Shilpa R Tekula^{1

2}, Suny Kim¹, Natasha Medhora¹, Shoshana A Leflein¹, Jacob Itkin¹, Raymond Trievel⁵, Kelley M Kidwell^{2

6}, Yu-Chih Chen⁷, Loredana Mauro³, Euisik Yoon⁸, Sebastiano Andò³, Celina G Kleer^{1

2}

Affiliations

¹ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
³ Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy.
⁴ Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA.
⁵ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁷ UPMC Hillman Cancer Center, Department of Computational and Systems Biology, Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
⁸ Department of Electrical Engineering and Computer Science and Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.

Abstract

Triple-negative breast cancers (TNBCs) are frequently poorly differentiated with high propensity for metastasis. Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 that mediates transcriptional repression in normal cells and in cancer through H3K27me3. However, H3K27me3-independent non-canonical functions of EZH2 are incompletely understood. We reported that EZH2 phosphorylation at T367 by p38α induces TNBC metastasis in an H3K27me3-independent manner. Here, we show that cytosolic EZH2 methylates p38α at lysine 139 and 165 leading to enhanced p38α stability and that p38 methylation and activation require T367 phosphorylation of EZH2. Dual inhibition of EZH2 methyltransferase and p38 kinase activities downregulates pEZH2-T367, H3K27me3, and p-p38 pathways in vivo and reduces TNBC growth and metastasis. These data uncover a cooperation between EZH2 canonical and non-canonical mechanisms and suggest that inhibition of these pathways may be a potential therapeutic strategy.

Keywords: Cancer; Epigenetics; Molecular biology.

Abstract

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