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Histone deacetylases, Mbd3/NuRD, and Tet2 hydroxylase are crucial regulators of epithelial–mesenchymal plasticity and tumor metastasis

Oncogene volume 39, pages 1498–1513 (2020)Cite this article

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Abstract

An epithelial–mesenchymal transition (EMT) represents a basic morphogenetic process of high cell plasticity underlying embryogenesis, wound healing, cancer metastasis and drug resistance. It involves a profound transcriptional and epigenetic reprogramming of cells. A critical role of epigenetic modifiers and their specific chromatin modifications has been demonstrated during EMT. However, it has remained elusive whether epigenetic control differs between the dynamic cell state transitions of reversible EMT and the fixed differentiation status of irreversible EMT. We have employed varying EMT models of murine breast cancer cells to identify the key players establishing epithelial–mesenchymal cell plasticity during reversible and irreversible EMT. We demonstrate that the Mbd3/NuRD complex and the activities of histone deacetylases (HDACs), and Tet2 hydroxylase play a critical role in keeping cancer cells in a highly metastatic mesenchymal state. Combinatorial interference with their functions leads to mesenchymal–epithelial transition (MET) and efficiently represses metastasis formation by invasive murine and human breast cancer cells in vivo.

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Data availability

Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Gerhard Christofori (gerhard.christofori@unibas.ch). The RNA sequencing data are deposited at Gene Expression Omnibus (GEO accession number: GSE100553).

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Acknowledgements

We thank P. Schär and S. Weis (DBM Basel) for reagents and protocols, F. Noreen (DBM Basel) for pyrosequencing, C. Beisel (D-BSSE, ETH Zürich) for next generation RNA sequencing, P. Lorentz (DBM Basel) for excellent microscopy support, and Isabel Galm for technical support.

Funding

This work was supported by the SystemsX.ch RTD project Cellplasticity, the SystemsX.ch MTD project MetastasiX, the Swiss National Science Foundation, and the Swiss Cancer League. MKJ was also supported by a training fellowship from the Gulf Coast Consortia on the Computational Cancer Biology Training Program (CPRIT Grant No. RP170593).

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Authors and Affiliations

  1. Department of Biomedicine, University of Basel, 4058, Basel, Switzerland

    Ayse Nihan Kilinc, Nami Sugiyama, Ravi Kiran Reddy Kalathur, Helena Antoniadis, Huseyin Birogul, Dana Ishay-Ronen & Gerhard Christofori

  2. Department of Chemical & Biological Engineering, Princeton University, 303 Hoyt Laboratory, William Street, Princeton, NJ, 08544, USA

    Ayse Nihan Kilinc

  3. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA

    Jason T. George & Herbert Levine

  4. Medical Science Training Program, Baylor College of Medicine, Houston, TX, USA

    Jason T. George

  5. Departments of Bioengineering and Physics, Northeastern University, Boston, MA, 02115, USA

    Herbert Levine

  6. Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012, India

    Mohit Kumar Jolly

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Contributions

ANK designed and performed the experiments, analyzed the data and wrote the paper; NS performed experiments for revision, RKRK performed bioinformatics analysis; HA performed animal experiments; HB analyzed animal experiments, DI-R performed Py2T MET Time-course, JTG, HL and MKJ performed EMT score analysis; and GC oversaw the project, designed experiments, analyzed the data and wrote the paper.

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Correspondence to Gerhard Christofori.

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Nihan Kilinc, A., Sugiyama, N., Reddy Kalathur, R.K. et al. Histone deacetylases, Mbd3/NuRD, and Tet2 hydroxylase are crucial regulators of epithelial–mesenchymal plasticity and tumor metastasis. Oncogene 39, 1498–1513 (2020). https://doi.org/10.1038/s41388-019-1081-2

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