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

Urbain Weyemi,Daisuke Maeda,Myriem Boufraqech,Vinodh N Rajapakse,Rohini Choudhuri,Taresh K Sethi,William M Bonner,Towqir Aziz,Palak R Parekh,Christophe E Redon,Natalie Abrams,Manjula Kasoji,Anand Merchant

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.

Highlights

The epithelial–mesenchymal transition (EMT), considered essential for metastatic cancer, has been a focus of much research, but important questions remain
It has been reported that histone H2A variant macroH2A is a critical component of chromatin that suppresses the progression of melanoma[15]
We observed that when cultures of the human colon cancer line HCT116 were made deficient in histone H2A.X, they lost their epithelial shape, became more mesenchymal-like (Fig. 1a), and more invasive (Fig. 1b)

Summary

Introduction

The epithelial–mesenchymal transition (EMT), considered essential for metastatic cancer, has been a focus of much research, but important questions remain. Our results point to Slug and ZEB1 as key EMT-related transcription factors regulated by H2A.X in colon cancer cells.

Results

Conclusion