Twist1 and Slug Mediate H2AX-regulated Epithelial-Mesenchymal Transition in Breast Cells

Cell Cycle. 2016 Sep 16;15(18):2398-404. doi: 10.1080/15384101.2016.1198864. Epub 2016 Jun 17.

Abstract

The epithelial-mesenchymal transition (EMT) is thought to be essential for cancer metastasis. While chromatin remodeling is involved in EMT, which processes contribute to this remodeling remain poorly investigated. Recently, we showed that silencing or removal of the histone variant H2A.X induced mesenchymal-like characteristics, including activation of the EMT transcription factors, Slug and Zeb1 in human colon cancer cells. Here, we provide the evidence that H2A.X loss in human non-tumorigenic breast cell line MCF10A results in a robust EMT activation, as substantiated by a genome-wide expression analysis. Cells deficient for H2A.X exhibit enhanced migration and invasion, along with an activation of a set of mesenchymal genes and a concomitant repression of epithelial genes. In the breast model, the EMT-related transcription factor Twist1 cooperates with Slug to regulate EMT upon H2A.X Loss. Of interest, H2A.X expression level tightly correlates with Twist1, and to a lesser extent with Slug in the panel of human breast cancer cell lines of the NCI-60 datasets. These new findings indicate that H2A.X is involved in the EMT processes in cells of different origins but pairing with transcription factors for EMT may be tissue specific.

Keywords: EMT; Slug; Twist1; breast cancer; histone H2AX.

MeSH terms

  • Breast / metabolism
  • Breast / pathology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition* / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Histones / metabolism*
  • Humans
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Snail Family Transcription Factors / metabolism*
  • Twist-Related Protein 1 / metabolism*

Substances

  • H2AX protein, human
  • Histones
  • Nuclear Proteins
  • Snail Family Transcription Factors
  • TWIST1 protein, human
  • Twist-Related Protein 1