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

Nature Communications
Talha AnwarCelina G Kleer

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.

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Citations

Sep 6, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Juraj AdamikDeborah L Galson
May 29, 2020·Science Translational Medicine·Lin ZhangDihua Yu
Mar 11, 2020·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Talha AnwarCelina G Kleer
Sep 9, 2020·Cell Death and Differentiation·Zhongwei LiJin Bai
Jul 28, 2020·Biomolecules·Alexandre PerrierSimon Garinet
Nov 29, 2020·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Emily R McMullenCelina G Kleer
Apr 27, 2019·Molecular Cancer Research : MCR·Justin Korfhage, David B Lombard
Nov 17, 2020·Frontiers in Oncology·Donglu WuHaoming Luo
Dec 15, 2020·Cell & Bioscience·Zhongwei LiJin Bai
Dec 18, 2020·International Journal of Molecular Sciences·Jun Wang, Gang Greg Wang
Jan 29, 2021·Nature Reviews. Molecular Cell Biology·Begoña Canovas, Angel R Nebreda
Feb 23, 2021·Cancer Science·Jinhua HuangTiejun Zhao
Feb 27, 2020·Bioorganic & Medicinal Chemistry·Zhong WanYongsheng Yu
Mar 11, 2021·PloS One·Laura V BownesElizabeth A Beierle
Mar 19, 2021·Frontiers in Cardiovascular Medicine·Shun WangZhihua Wang
Mar 21, 2021·Nature Communications·Liliana Garcia-MartinezLluis Morey
Feb 9, 2021·The American Journal of Pathology·Talha AnwarCelina G Kleer
Mar 23, 2021·Communications Biology·Kyrie PappasRamon Parsons
Jun 1, 2021·Computational and Mathematical Methods in Medicine·Yongxiong HeHongwei Yuan
Jun 24, 2021·Epigenetics : Official Journal of the DNA Methylation Society·Rieke SchröderJesús Duque-Afonso
Jul 17, 2021·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Xiujuan Zhao, Xudong Wu

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Datasets Mentioned

BETA
PXD010073

Methods Mentioned

BETA
dot blot
chip
immunoprecipitation
pulldown
proximity ligation
co-immunoprecipitation
xenografts
sizing fractionation
PCR
biosensors

Software Mentioned

Living Image
SAINTexpress
CRAPome
R
MATLAB
DAVID
PANTHER
Powerpoint
SAINT
VennDiagram

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