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The epigenetics of epithelial-mesenchymal plasticity in cancer

Abstract

During the course of malignant cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, the extremes of which are defined by the expression of epithelial and mesenchymal phenotypes. This plasticity is enabled by underlying shifts in epigenetic regulation. A small cohort of pleiotropically acting transcription factors is widely recognized to effect these shifts by controlling the expression of a constituency of key target genes. These master regulators depend on complex epigenetic regulatory mechanisms, notably the induction of changes in the modifications of chromatin-associated histones, in order to achieve the widespread changes in gene expression observed during epithelial-mesenchymal transitions (EMTs). These associations indicate that an understanding of the functional interactions between such EMT-inducing transcription factors and the modulators of chromatin configuration will provide crucial insights into the fundamental mechanisms underlying cancer progression and may, in the longer term, generate new diagnostic and therapeutic modalities for treating high-grade malignancies.

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Figure 1: Connecting extracellular signals to EMT transcription factors.
Figure 2: Epithelial-mesenchymal plasticity allows cancer cells to undergo functional adaptations during the invasion-metastasis cascade.
Figure 3: The epigenetic landscape governs the stability of epithelial-mesenchymal plasticity.
Figure 4: Interactions between transcription factors and epigenetic regulators.
Figure 5: Integral microRNA transcription regulator networks control epithelial-mesenchymal plasticity.

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Acknowledgements

We thank J.A. Krall for helpful comments and T. DiCesare for illustrations. Research in the Weinberg laboratory is supported by grants from the US National Institutes of Health (P01 CA080111), the Breast Cancer Research Foundation, MIT Ludwig Center for Molecular Oncology and the Cotswold Trust. R.A.W. is an American Cancer Society and Ludwig Foundation professor. W.L.T. is supported by the MIT Ludwig Center for Molecular Oncology.

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Tam, W., Weinberg, R. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19, 1438–1449 (2013). https://doi.org/10.1038/nm.3336

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