Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers
The active acquisition of epigenetic changes is a poorly understood but important process in development, differentiation, and disease. Our work has shown that repression of the p16/pRb pathway in human epithelial cells, a condition common to stem cells and many tumor cells, induces dynamic epigenet...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 39; pp. 14867 - 14872 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
30.09.2008
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | The active acquisition of epigenetic changes is a poorly understood but important process in development, differentiation, and disease. Our work has shown that repression of the p16/pRb pathway in human epithelial cells, a condition common to stem cells and many tumor cells, induces dynamic epigenetic remodeling resulting in the targeted methylation of a selected group of CpG islands. We hypothesized that cells in this epigenetically plastic state could be programmed by the microenvironment to acquire epigenetic changes associated with tumorigenesis. Here, we describe an in vitro model system where epigenetically plastic cells were placed in an environment that induced epithelial to mesenchymal transition (EMT) and led to a program of acquired de novo DNA methylation at targeted sites. In this model, we found that repression of E-cadherin transcription preceded the subsequent acquisition of methylated CpG sites. Furthermore, the induction of EMT was accompanied by de novo methylation of several other gene promoters, including those of the estrogen receptor and Twist. These data demonstrate that signals from the microenvironment can induce phenotypic and gene expression changes associated with targeted de novo epigenetic alterations important in tumor progression, and that these alterations occur through a deterministic, rather than stochastic, mechanism. Given the dynamic epigenetic reprogramming that occurs in these cells, DNA methylation profiles observed in human tumors may reflect the history of environmental exposures during the genesis of a tumor. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Author contributions: N.D. and T.D.T. designed research; N.D., M.B.W., Y.G.C., P.A.R., and M.S. performed research; N.D. analyzed data; and N.D. and T.D.T. wrote the paper. Present address: University of St. Andrews, Bute Medical School, St. Andrews KY16 9TS, Scotland. Present address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Communicated by Joan S. Brugge, Harvard Medical School, Boston, MA, July 31, 2008 |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0807146105 |