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

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

doi:10.1038/ncomms10711

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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English (US)
Article number	10711
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10711
State	Published - Feb 15 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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@article{aedae333c006423b80369d7d4957f1a8,

title = "The histone variant H2A.X is a regulator of the epithelial-mesenchymal transition",

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.",

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

note = "Funding Information: We thank Drs Simone Difilippantonio, Diana Haines and Joseph D. Kalen, Mr. Nimit Patel, Mrs. Christina Robinson and the other members of the Laboratory of Animal Sciences Program (National Cancer Institute, Frederick) for help with animal maintenance, tail vein injections experiments and histological analysis. We are grateful to Drs Farhoud Faraji, Andrea Baechler, Anjali A. Shukla and Sudhir Varma for their helpful discussions. We also thank Mrs Jennifer E. Dwyer and Mrs Shelley Hoover of the Laboratory of Cancer Biology and Genetics (National Cancer Institute) for help with scanning of immunohistochemistry slides. We are indebted to members of the LMT/ Affymetrix Group, NCI-Frederick, MD,USA, for their help with microarray runs (Affymetrix GeneChip Human Gene 2.0 ST array). We are particularly grateful to Drs Karen M. Wolcott, Subhadra Banerjee and Ludmila Krymskaya, for help with flow cytometry (cells sorting). Finally, we thank Mr Owen K. Smith for the critical reading of the manuscript; Mrs Houria Balmakhtar for help with experiments; and Mr. Parthav Jailwala for help with microarray data analysis. This work was supported by the National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health.",

year = "2016",

month = feb,

day = "15",

doi = "10.1038/ncomms10711",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

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TY - JOUR

T1 - The histone variant H2A.X is a regulator of the epithelial-mesenchymal transition

AU - Weyemi, Urbain

AU - Redon, Christophe E.

AU - Choudhuri, Rohini

AU - Aziz, Towqir

AU - Maeda, Daisuke

AU - Boufraqech, Myriem

AU - Parekh, Palak R.

AU - Sethi, Taresh K.

AU - Kasoji, Manjula

AU - Abrams, Natalie

AU - Merchant, Anand

AU - Rajapakse, Vinodh N.

AU - Bonner, William M.

N1 - Funding Information: We thank Drs Simone Difilippantonio, Diana Haines and Joseph D. Kalen, Mr. Nimit Patel, Mrs. Christina Robinson and the other members of the Laboratory of Animal Sciences Program (National Cancer Institute, Frederick) for help with animal maintenance, tail vein injections experiments and histological analysis. We are grateful to Drs Farhoud Faraji, Andrea Baechler, Anjali A. Shukla and Sudhir Varma for their helpful discussions. We also thank Mrs Jennifer E. Dwyer and Mrs Shelley Hoover of the Laboratory of Cancer Biology and Genetics (National Cancer Institute) for help with scanning of immunohistochemistry slides. We are indebted to members of the LMT/ Affymetrix Group, NCI-Frederick, MD,USA, for their help with microarray runs (Affymetrix GeneChip Human Gene 2.0 ST array). We are particularly grateful to Drs Karen M. Wolcott, Subhadra Banerjee and Ludmila Krymskaya, for help with flow cytometry (cells sorting). Finally, we thank Mr Owen K. Smith for the critical reading of the manuscript; Mrs Houria Balmakhtar for help with experiments; and Mr. Parthav Jailwala for help with microarray data analysis. This work was supported by the National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health.

PY - 2016/2/15

Y1 - 2016/2/15

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms10711

DO - 10.1038/ncomms10711

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VL - 7

JO - Nature communications

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

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