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

Nat Commun. 2018 Jul 18;9(1):2801. doi: 10.1038/s41467-018-05078-8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Carcinoma, Ductal, Breast / genetics*
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / secondary
  • Carcinoma, Ductal, Breast / therapy
  • Cell Line, Tumor
  • Cell Movement
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Heterografts
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Mice
  • Mice, SCID
  • Phosphorylation
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Survival Analysis
  • Threonine
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Histones
  • RNA, Small Interfering
  • Threonine
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • p38 Mitogen-Activated Protein Kinases