TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells

Horacio Cardenas, Edyta Vieth, Jiyoon Lee, Mathew Segar, Yunlong Liu, Kenneth Nephew, Daniela Matei

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1461-1472
Number of pages12
JournalEpigenetics : official journal of the DNA Methylation Society
Volume9
Issue number11
DOIs
StatePublished - Dec 18 2014

Fingerprint

Epithelial-Mesenchymal Transition
DNA Methylation
Ovarian Neoplasms
Methylation
Epigenomics
Genes
Cytokines
Neoplasm Metastasis
CpG Islands
DNA
Methyltransferases
Cadherins
Neoplasms
Cell Survival
Cell Cycle
Cell Death
Collagen
Gene Expression

Keywords

  • DNA methylation
  • EMT
  • Ovarian cancer
  • SGI-110
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Medicine(all)

Cite this

TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells. / Cardenas, Horacio; Vieth, Edyta; Lee, Jiyoon; Segar, Mathew; Liu, Yunlong; Nephew, Kenneth; Matei, Daniela.

In: Epigenetics : official journal of the DNA Methylation Society, Vol. 9, No. 11, 18.12.2014, p. 1461-1472.

Research output: Contribution to journalArticle

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