TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells.
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.
['Cardenas|Horacio|H|', 'Vieth|Edyta|E|', 'Lee|Jiyoon|J|', 'Segar|Mathew|M|', 'Liu|Yunlong|Y|', 'Nephew|Kenneth P|KP|', 'Matei|Daniela|D|']
D015703:Antigens, CD D001374:Azacitidine D015820:Cadherins D045744:Cell Line, Tumor D024042:Collagen Type I D000090602:Collagen Type I, alpha 1 Chain D018899:CpG Islands D000076123:DNA (Cytosine-5-)-Methyltransferase 1 D004248:DNA (Cytosine-5-)-Methyltransferases D019175:DNA Methylation D000090205:DNA Methyltransferase 3A D004791:Enzyme Inhibitors D044127:Epigenesis, Genetic D058750:Epithelial-Mesenchymal Transition D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D010051:Ovarian Neoplasms D011401:Promoter Regions, Genetic D016212:Transforming Growth Factor beta
TGF-β DNA methylation ovarian cancer EMT SGI-110 15 DNMTI, DNMT inhibitor CGI, CpG island DNMT, DNA methyltransferase EMT, epithelial-to-mesenchymal transition HMA, hypomethylating agent IPA, Ingenuity pathway analysis PCA, principal component analysis TGF-b, transforming growth factor b TSS, transcription start site mRNA, messenger ribonucleic acid