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.
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Urbain
authors.initials: U
authors.lastname: Weyemi
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Rohini
authors.initials: R
authors.lastname: Choudhuri
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Towqir
authors.initials: T
authors.lastname: Aziz
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Myriem
authors.initials: M
authors.lastname: Boufraqech
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Palak R
authors.initials: PR
authors.lastname: Parekh
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Taresh K
authors.initials: TK
authors.lastname: Sethi
authors.affiliation: Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Kasoji
authors.affiliation: Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Abrams
authors.affiliation: Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Merchant
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Vinodh N
authors.initials: VN
authors.lastname: Rajapakse
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C468783:H2AX protein, human; D006657:Histones; D018398:Homeodomain Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1