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
Affiliations
Maria E. Gonzalez
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Giuseppina Daniela Naimo
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy
Talha Anwar
Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
Alessandro Paolì
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy
Shilpa R. Tekula
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
Suny Kim
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Natasha Medhora
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Shoshana A. Leflein
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Jacob Itkin
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Raymond Trievel
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA
Kelley M. Kidwell
Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
Yu-Chih Chen
UPMC Hillman Cancer Center, Department of Computational and Systems Biology, Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA
Loredana Mauro
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy
Euisik Yoon
Department of Electrical Engineering and Computer Science and Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
Sebastiano Andò
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy
Celina G. Kleer
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Corresponding author
Summary: 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.
