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SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of β1-integrin

Nature Cell Biology volume 11, pages 557–568 (2009)Cite this article

Abstract

Gene expression reprogramming governs cellular processes such as proliferation, differentiation and cell migration through the complex and tightly regulated control of transcriptional cofactors that exist in multiprotein complexes. Here we describe SCAI (suppressor of cancer cell invasion), a novel and highly conserved protein that regulates invasive cell migration through three-dimensional matrices. SCAI acts on the RhoA–Dia1 signal transduction pathway and localizes in the nucleus, where it binds and inhibits the myocardin-related transcription factor MAL by forming a ternary complex with serum response factor (SRF). Genome-wide expression analysis surprisingly reveals that one of the strongest upregulated genes after suppression of SCAI is β1-integrin. Decreased levels of SCAI are tightly correlated with increased invasive cell migration, and SCAI is downregulated in several human tumours. Functional analysis of the β1-integrin gene strongly argues that SCAI is a novel transcriptional cofactor that controls gene expression downstream of Dia1 to dictate changes in cell invasive behaviour.

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Figure 1: Identification and expression of SCAI.
Figure 2: SCAI inhibits the SRF coactivator MAL.
Figure 3: Interaction of SCAI with MAL.
Figure 4: SCAI inhibitory activity requires its nuclear localization.
Figure 5: Nuclear SCAI forms a complex with MAL–SRF.
Figure 6: SCAI controls cancer cell invasion into three-dimensional Matrigel.
Figure 7: SCAI is a potent regulator of β1-integrin.
Figure 8: SCAI controls the β1-integrin gene through MAL and SRF.

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Acknowledgements

We thank B. Di Ventura and W. Birchmeier for critical reading, and R. Treisman and T. Worzfeld for stimulating discussions. We are grateful to A. Ripperger, K. Reeck and G. Streichert for technical assistance, and U. Engel at the Nikon Imaging Center for imaging advice. This work was funded by the Emmy Noether Program of the Deutsche Forschungsgemeinschaft (GR 2111/1-3) and the Wilhelm Sander-Stiftung (2008.020.1) to R.G. R.G. is a member of the excellence cluster Cellular Networks and supported by the CHS Foundation. J.I. is supported by the EMBO Young Investigator Program, Academy of Finland, and the European Research Council.

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Author notes

  1. Dominique T. Brandt and Christian Baarlink: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany

    Dominique T. Brandt, Christian Baarlink, Thomas M. Kitzing & Robert Grosse

  2. Helmholtz Zentrum München, Institute of Molecular Immunology, Marchionistrasse 25, Munich, 81377, Germany

    Elisabeth Kremmer

  3. VTT Technical Research Centre of Finland and University of Turku, Turku, FIN-20520, Finland

    Johanna Ivaska

  4. Department of Clinical Chemistry, Center of Clinical Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany

    Peter Nollau

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Contributions

D.T.B. and C.B. designed, performed and analysed the majority of experiments; T.M.K. generated data in Figs 6 and 7. E.K. generated monoclonal antibodies against SCAI; J.I. generated the data in Fig. 7d, and P.N. the data in Fig. 7a. R.G. generated data in Fig. 5, designed and discussed experiments and wrote the manuscript.

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Correspondence to Robert Grosse.

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Brandt, D., Baarlink, C., Kitzing, T. et al. SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of β1-integrin. Nat Cell Biol 11, 557–568 (2009). https://doi.org/10.1038/ncb1862

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