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Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function

Oncogene volume 34, pages 53–62 (2015)Cite this article

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Abstract

Tumor cell invasion is a major contributor to cancer morbidity, and is of particular importance in patients with glioblastoma multiforme (GBM), the highest grade and most aggressive primary brain tumor. Tumor cell invasion and the expression of matrix metalloproteinases (MMPs), which are required for GBM invasion, are enhanced by inhibitor of DNA binding (Id) gene family members, Id1, Id2 and Id3, which can be highly expressed in glioma. Id4 is expressed in GBM at more variable levels than these other family members and we sought to determine its role in invasion. We found, unexpectedly, that invasion was dramatically inhibited in cells expressing Id4 as a result of decreased MMP2, a secreted proteinase key for brain tumor invasion. We demonstrate that Id4 decreased MMP2 expression by a direct inhibitory interaction with Twist1, a basic helix-loop-helix transcription factor known to increase MMP2 expression. Importantly, using data from The Cancer Genome Atlas, we show that Id4 expression correlates with survival of glioblastoma patients and inversely correlates with MMP2 expression. These data suggest that the upregulation of MMP2 resulting from decreased Id4 expression in GBM may contribute to the morbidity and mortality of GBM patients.

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Acknowledgements

We thank Dr Constance Brinckerhoff for assisting in the development of the project and for providing antibodies to MMP1, 3 and 13. We are grateful for all the Israel Laboratory members for stimulating discussion, especially Dr Zhonghua Zhang for his expert opinions. We thank Dr Constance Brinckerhoff, Dr Zhonghua Zhang, Pranam Chatterjee and Ilenna Jones for their help on preparing the manuscript. We would like to thank Kenneth A Orndorff from the shared fluorescence imaging core at the Norris Cotton Cancer Center for his expert advice on confocal images. We thank Dr Christopher Dant and Ms Tabatha Richardson at Dartmouth for their editorial advice. This work is supported by the Hitchcock Foundation (GJR), the Jordan and Kyra Memorial Foundation (MAI) and the Theodora B. Betz Foundation (MAI).

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Authors and Affiliations

  1. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    G J Rahme & M A Israel

  2. Department of Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    M A Israel

  3. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    G J Rahme & M A Israel

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Correspondence to M A Israel.

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Rahme, G., Israel, M. Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function. Oncogene 34, 53–62 (2015). https://doi.org/10.1038/onc.2013.531

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