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Tenascin-C Is a Novel RBPJ-Induced Target Gene for Notch Signaling in Gliomas

¹ Laboratory of Molecular Neuro-Oncology, Department of Research, ² Neurosurgical Clinic, ³ Institute of Pathology, ⁴ Laboratory of Prenatal Medicine, Department of Research, University Hospital, and ⁵ Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland; ⁶ Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Centre Universitaire Romand de Neurochirurgie, and University of Lausanne, Lausanne, Switzerland; ⁷ National Center of Competence in Research, Molecular Oncology, Institut Suisse de Recherche Expérimentale sur le Cancer, SLS-EPFL, Epalinges, Switzerland; ⁸ Research Laboratories, diagene, Inc., Reinach, Switzerland; and ⁹ Laboratory of Toxicology, Institute of Pharmacy, Free University, Brussels, Belgium

Requests for reprints: Ruth Chiquet-Ehrismann, Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Phone: 41-61-697-24-94; Fax: 41-61-697-39-76; E-mail: Ruth.Chiquet{at}fmi.ch.

Key Words: Notch signaling • Tenascin-C • cancer • brain • cell migration

Tenascin-C (TNC) expression is known to correlate with malignancy in glioblastoma (GBM), a highly invasive and aggressive brain tumor that shows limited response to conventional therapies. In these malignant gliomas as well as in GBM cell lines, we found Notch2 protein to be strongly expressed. In a GBM tumor tissue microarray, RBPJk protein, a Notch2 cofactor for transcription, was found to be significantly coexpressed with TNC. We show that the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. The transactivation is abrogated by a Notch2 mutation, which we detected in the glioma cell line Hs683 that does not express TNC. This L1711M mutation resides in the RAM domain, the site of interaction between Notch2 and RBPJk. In addition, transfection of constructs encoding activated Notch2 or Notch1 increased endogenous TNC expression identifying TNC as a novel Notch target gene. Overexpression of a dominant negative form of the transcriptional coactivator MAML1 or knocking down RBPJk in LN319 cells led to a dramatic decrease in TNC protein levels accompanied by a significant reduction of cell migration. Because addition of purified TNC stimulated glioma cell migration, this represents a mechanism for the invasive properties of glioma cells controlled by Notch signaling and defines a novel oncogenic pathway in gliomagenesis that may be targeted for therapeutic intervention in GBM patients. [Cancer Res 2009;69(2):458–65]