title: Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of Snail-1.
abstract: Epithelial-mesenchymal transition (EMT) is thought to contribute to cancer metastasis, but its underlying mechanisms are not well understood. To define early steps in this cellular transformation, we analyzed human mammary epithelial cells with tightly regulated expression of Snail-1, a master regulator of EMT. After Snail-1 induction, epithelial markers were repressed within 6 hr, and mesenchymal genes were induced at 24 hr. Snail-1 binding to its target promoters was transient (6-48 hr) despite continued protein expression, and it was followed by both transient and long-lasting chromatin changes. Pharmacological inhibition of selected histone acetylation and demethylation pathways suppressed the induction as well as the maintenance of Snail-1-mediated EMT. Thus, EMT involves an epigenetic switch that may be prevented or reversed with the use of small-molecule inhibitors of chromatin modifiers.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Javaid
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Endre
authors.initials: E
authors.lastname: Anderssen
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Josh C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Gromoslaw A
authors.initials: GA
authors.lastname: Smolen
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zubrowski
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Rushil
authors.initials: R
authors.lastname: Desai
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: haber@helix.mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000107:Acetylation; D063646:Carcinogenesis / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008745:Methylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D006655:Histone Deacetylases