Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming

Neha Tiwari; Vijay K Tiwari; Lorenz Waldmeier; Piotr J Balwierz; Phil Arnold; Mikhail Pachkov; Nathalie Meyer-Schaller; Dirk Schübeler; Erik van Nimwegen; Gerhard Christofori

doi:10.1016/j.ccr.2013.04.020

Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming

Cancer Cell. 2013 Jun 10;23(6):768-83. doi: 10.1016/j.ccr.2013.04.020.

Authors

Neha Tiwari¹, Vijay K Tiwari, Lorenz Waldmeier, Piotr J Balwierz, Phil Arnold, Mikhail Pachkov, Nathalie Meyer-Schaller, Dirk Schübeler, Erik van Nimwegen, Gerhard Christofori

Affiliation

¹ Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.

PMID: 23764001
DOI: 10.1016/j.ccr.2013.04.020

Abstract

Gene expression profiling has uncovered the transcription factor Sox4 with upregulated activity during TGF-β-induced epithelial-mesenchymal transition (EMT) in normal and cancerous breast epithelial cells. Sox4 is indispensable for EMT and cell survival in vitro and for primary tumor growth and metastasis in vivo. Among several EMT-relevant genes, Sox4 directly regulates the expression of Ezh2, encoding the Polycomb group histone methyltransferase that trimethylates histone 3 lysine 27 (H3K27me3) for gene repression. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT in Sox4-deficient cells. Ezh2-mediated H3K27me3 marks associate with key EMT genes, representing an epigenetic EMT signature that predicts patient survival. Our results identify Sox4 as a master regulator of EMT by governing the expression of the epigenetic modifier Ezh2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Movement / genetics
Cell Survival / genetics
Enhancer of Zeste Homolog 2 Protein
Epigenesis, Genetic*
Epithelial-Mesenchymal Transition*
Female
Gene Expression Regulation, Neoplastic*
Histones / metabolism
Humans
MCF-7 Cells
Mammary Neoplasms, Experimental / genetics*
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Methylation
Mice
Neoplasm Metastasis / genetics
Polycomb Repressive Complex 2 / genetics*
Polycomb Repressive Complex 2 / metabolism
Polycomb Repressive Complex 2 / physiology
Promoter Regions, Genetic
SOXC Transcription Factors / genetics
SOXC Transcription Factors / metabolism
SOXC Transcription Factors / physiology*
Transcription, Genetic

Substances

Histones
SOXC Transcription Factors
Sox4 protein, mouse
Enhancer of Zeste Homolog 2 Protein
Ezh2 protein, mouse
Polycomb Repressive Complex 2

Associated data

GEO/GSE44050
GEO/GSE45579