title: TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells.
abstract: A key step in the process of metastasis is the epithelial-to-mesenchymal transition (EMT). We hypothesized that epigenetic mechanisms play a key role in EMT and to test this hypothesis we analyzed global and gene-specific changes in DNA methylation during TGF-β-induced EMT in ovarian cancer cells. Epigenetic profiling using the Infinium HumanMethylation450 BeadChip (HM450) revealed extensive (P < 0.01) methylation changes after TGF-β stimulation (468 and 390 CpG sites altered at 48 and 120 h post cytokine treatment, respectively). The majority of gene-specific TGF-β-induced methylation changes occurred in CpG islands located in or near promoters (193 and 494 genes hypermethylated at 48 and 120 h after TGF-β stimulation, respectively). Furthermore, methylation changes were sustained for the duration of TGF-β treatment and reversible after the cytokine removal. Pathway analysis of the hypermethylated loci identified functional networks strongly associated with EMT and cancer progression, including cellular movement, cell cycle, organ morphology, cellular development, and cell death and survival. Altered methylation and corresponding expression of specific genes during TGF-β-induced EMT included CDH1 (E-cadherin) and COL1A1 (collagen 1A1). Furthermore, TGF-β induced both expression and activity of DNA methyltransferases (DNMT) -1, -3A, and -3B, and treatment with the DNMT inhibitor SGI-110 prevented TGF-β-induced EMT. These results demonstrate that dynamic changes in the DNA methylome are implicated in TGF-β-induced EMT and metastasis. We suggest that targeting DNMTs may inhibit this process by reversing the EMT genes silenced by DNA methylation in cancer.
authors.affiliation: a Department of Medicine ; Indiana University School of Medicine ; Indianapolis , IN USA.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cardenas
authors.forename: Edyta
authors.initials: E
authors.lastname: Vieth
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Lee
authors.forename: Mathew
authors.initials: M
authors.lastname: Segar
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
mesh_terms: D015703:Antigens, CD; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D018899:CpG Islands / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D000097584:DNA Methyltransferase 3B
chemical_list: D015703:Antigens, CD; D001374:Azacitidine; D015820:Cadherins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D000097584:DNA Methyltransferase 3B; C513384:CDH1 protein, human; C000717967:DNMT3A protein, human; C580831:guadecitabine
keywords: 15 DNMTI, DNMT inhibitor; CGI, CpG island; DNA methylation; DNMT, DNA methyltransferase; EMT; EMT, epithelial-to-mesenchymal transition; HMA, hypomethylating agent; IPA, Ingenuity pathway analysis; PCA, principal component analysis; SGI-110; TGF-b, transforming growth factor b; TGF-β; TSS, transcription start site; mRNA, messenger ribonucleic acid; ovarian cancer