title: The high mobility group A2 protein epigenetically silences the Cdh1 gene during epithelial-to-mesenchymal transition.
abstract: The loss of the tumour suppressor E-cadherin (Cdh1) is a key event during tumourigenesis and epithelial-mesenchymal transition (EMT). Transforming growth factor-β (TGFβ) triggers EMT by inducing the expression of non-histone chromatin protein High Mobility Group A2 (HMGA2). We have previously shown that HMGA2, together with Smads, regulate a network of EMT-transcription factors (EMT-TFs) like Snail1, Snail2, ZEB1, ZEB2 and Twist1, most of which are well-known repressors of the Cdh1 gene. In this study, we show that the Cdh1 promoter is hypermethylated and epigenetically silenced in our constitutive EMT cell model, whereby HMGA2 is ectopically expressed in mammary epithelial NMuMG cells and these cells are highly motile and invasive. Furthermore, HMGA2 remodels the chromatin to favour binding of de novo DNA methyltransferase 3A (DNMT3A) to the Cdh1 promoter. E-cadherin expression could be restored after treatment with the DNA de-methylating agent 5-aza-2'-deoxycytidine. Here, we describe a new epigenetic role for HMGA2, which follows the actions that HMGA2 initiates via the EMT-TFs, thus achieving sustained silencing of E-cadherin expression and promoting tumour cell invasion.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden.
authors.forename: E-Jean
authors.initials: EJ
authors.lastname: Tan
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kahata
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Idås
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thuault
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala SE-75123, Sweden aris.moustakas@imbim.uu.se.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D015703:Antigens, CD; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D025743:HMGA2 Protein / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D000076246:CCCTC-Binding Factor; C513384:CDH1 protein, human; C000619697:CTCF protein, human; D015820:Cadherins; C000717967:DNMT3A protein, human; D025743:HMGA2 Protein; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine