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Basonuclin-1 modulates epithelial plasticity and TGF-β1-induced loss of epithelial cell integrity

Oncogene volume 34, pages 1185–1195 (2015)Cite this article

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Abstract

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine and critically involved in the progression of a variety of cancers. TGF-β1 signaling can impair tumor development by its anti-proliferative and pro-apoptotic features. In contrast, it may actively promote tumor progression and cancer cell dissemination by inducing a gradual switch from epithelial towards mesenchymal-like cell features (EMT-like), including decreased intercellular adhesion. Here, we show that expression of the transcription factor Basonuclin-1 (Bnc1) modulates TGF-β1-induced epithelial dedifferentiation of mammary epithelial cells. RNAi-mediated repression of Bnc1 resulted in enhanced intercellular adhesion and strongly impaired TGF-β1-dependent sheet disintegration and cell scattering. In contrast, forced expression of Bnc1 modifies plasma membrane/cytoskeletal dynamics and seemingly interferes with the initiation of sustainable cell–cell contacts. Follow-up analyses revealed that Bnc1 affects the expression of numerous TGF-β1-responsive genes including distinct EMT-related transcription factors, some of which modulate the expression of Bnc1 themselves. These results suggest that Bnc1 is part of a transcription factor network related to epithelial plasticity with reciprocal feedback-loop connections on which Smad-factors integrate TGF-β1 signaling. Our study demonstrates that Bnc1 regulates epithelial plasticity of mammary epithelial cells and influences outcome of TGF-β1 signaling.

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Acknowledgements

We kindly acknowledge Peter ten Dijke, David Danielpour, Sebastian Diecke and Roderick Beijersbergen for generously providing cells and plasmids. Support by the DKFZ Light Microscopy Facility is gratefully acknowledged. We thank Maria Muciek for excellent assistance with regard to microarray expression profiling and Ann Na Tan for excellent technical support. This study was supported by a grant of the DFG (SFB-938) to HJG.

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Author notes

  1. A Feuerborn

    Present address: 4Current address: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK,

Authors and Affiliations

  1. Department of Cellular and Molecular Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany

    A Feuerborn, D Mathow & H-J Gröne

  2. Physiological Genomics and Medicine, MRC Clinical Sciences, Imperial College, London, UK

    P K Srivastava

  3. Department of Medical Research, Faculty of Medicine, Medical Research Centre (ZMF), University of Heidelberg, Mannheim, Germany

    N Gretz

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Correspondence to A Feuerborn or H-J Gröne.

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Feuerborn, A., Mathow, D., Srivastava, P. et al. Basonuclin-1 modulates epithelial plasticity and TGF-β1-induced loss of epithelial cell integrity. Oncogene 34, 1185–1195 (2015). https://doi.org/10.1038/onc.2014.54

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