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The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis

Oncogene volume 32, pages 1396–1407 (2013)Cite this article

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Abstract

Lethal giant larvae proteins have key roles in regulating polarity in a variety of cell types and function as tumour suppressors. A transcriptional programme initiated by aberrant Snail expression transforms epithelial cells to potentially aggressive cancer cells. Although progress in defining the molecular determinants of this programme has been made, we have little knowledge as to how the Snail-induced phenotype can be suppressed. In our studies we identified the human lethal giant larvae homologue 2, Hugl-2, (Llgl2/Lgl2) polarity gene as downregulated by Snail. Snail binds E-boxes in the Hugl-2 promoter and represses Hugl-2 expression, whereas removal of the E-boxes releases Hugl-2 from Snail repression. We demonstrate that inducing Hugl-2 in cells with constitutive Snail expression reverses the phenotype including changes in morphology, motility, tumour growth and dissemination in vivo, and expression of epithelial markers. Hugl-2 expression reduced the nuclear localization of Snail and thus binding of Snail to its target promoters. Our results placing Hugl-2 within the Snail network as well as its ability to suppress Snail carcinogenesis identifies Hugl-2 as a target molecule driving cascades, which may have preventative and therapeutic promise to minimize cancer progression.

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Acknowledgements

We thank A Garcia de Herreros for allowing us to use the Snail-HA expression plasmid and PH Krammer for providing anti-Apo-1 antibody. MDA-MB-231 cells were a gift of Thomas Efferth. We kindly thank Anil K Rustgi and Eric R Fearon for providing CyclinD1- and E-cadherin-luciferase constructs, respectively. The expert technical assistance of Mirjam Weisser, Daniela Gottfried, Henry Alizor, Shenchu Jin and Henning Janssen is gratefully acknowledged. Special thanks to the laser-scanning microscopy Core Facility of the Forschungszentrum Immunolgie Mainz. This work was supported by grants from the MAIFOR program to DS and SS. DS and SS should be considered as equal senior authors.

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Authors and Affiliations

  1. First Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany

    A Kashyap, T Zimmerman, N Ergül, U Hartman, V Alla, P R Galle, S Strand & D Strand

  2. Institute of Pathology, University Regensburg, Regensburg, Germany

    A Bosserhoff & F Bataille

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  1. A Kashyap
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Correspondence to D Strand.

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Kashyap, A., Zimmerman, T., Ergül, N. et al. The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis. Oncogene 32, 1396–1407 (2013). https://doi.org/10.1038/onc.2012.162

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