The histone variant H2A.X is a regulator of the epithelial-mesenchymal transition

Nat Commun. 2016 Feb 15;7:10711. doi: 10.1038/ncomms10711.

Abstract

The epithelial-mesenchymal transition (EMT), considered essential for metastatic cancer, has been a focus of much research, but important questions remain. Here, we show that silencing or removing H2A.X, a histone H2A variant involved in cellular DNA repair and robust growth, induces mesenchymal-like characteristics including activation of EMT transcription factors, Slug and ZEB1, in HCT116 human colon cancer cells. Ectopic H2A.X re-expression partially reverses these changes, as does silencing Slug and ZEB1. In an experimental metastasis model, the HCT116 parental and H2A.X-null cells exhibit a similar metastatic behaviour, but the cells with re-expressed H2A.X are substantially more metastatic. We surmise that H2A.X re-expression leads to partial EMT reversal and increases robustness in the HCT116 cells, permitting them to both form tumours and to metastasize. In a human adenocarcinoma panel, H2A.X levels correlate inversely with Slug and ZEB1 levels. Together, these results point to H2A.X as a regulator of EMT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma / genetics*
  • Animals
  • Blotting, Western
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics*
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Genetic Variation
  • HCT116 Cells
  • HEK293 Cells
  • Histones / genetics*
  • Homeodomain Proteins / genetics*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / genetics*
  • Neoplasm Transplantation
  • Real-Time Polymerase Chain Reaction
  • Snail Family Transcription Factors
  • Transcription Factors / genetics*
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • H2AX protein, human
  • Histones
  • Homeodomain Proteins
  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1