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Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

Oncogene volume 29, pages 5828–5838 (2010)Cite this article

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Abstract

The neuron-restrictive silencer factor/RE1-silencing transcription factor (NRSF/REST) is a negative regulator of gene expression restricting the expression of neuronal genes to the nervous system. NRSF/REST is highly expressed in non-neuronal tissues like the lung. In previous work, we identified small-cell lung cancer (SCLC) cell lines with no detectable NRSF/REST expression that, as a consequence, expressed neuronal markers like L1-cell adhesion molecule (L1-CAM) and neural cell adhesion molecule (NCAM). The loss of NRSF/REST expression was linked to malignant progression; however, its mechanistic role remained elusive. Here, we show that NRSF/REST itself, rather than one of its regulated genes, acts like a classic tumour suppressor, being in part regulated by methylation. In SCLCs, NRSF/REST is positively regulated by CREB, with an NRSF/REST promoter fragment showing cell type specificity. Downstream, NRSF/REST directly regulates AKT2, in which NRSF/REST loss leads to an epidermal growth factor-mediated de-regulation of AKT-Serine473 phosphorylation, important for cellular proliferation and survival. Assaying anchorage-independent growth, we observed that with reduced NRSF/REST expression, proliferation was significantly enhanced, whereas NRSF/REST rescue decreased the potential of cells to grow anchorage independently. Our observations support the fact that NRSF/REST may act as an important modulator of malignant progression in SCLC.

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Acknowledgements

We thank Barbara Orlicz-Welcz, Rosa Weber, Florentine Koppitz, Sonja Oeser and Eli Stiegler for dedicated technical assistance and the group of Michael Wegner for their help with the luciferase assays. We thank Magnus von Knebel-Doeberitz from the University of Heidelberg for the NRSF/REST expression vector pcNRSFwt. This project was supported by a grant from the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of University of Erlangen-Nürnberg to CM Becker and PL Strissel and a grant from the Johannes und Frieda Marohn-Stiftung.

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  1. Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany

    A Kreisler & C-M Becker

  2. Labor für Molekulare Medizin, Frauenklinik, Universitaetsklinikum, Erlangen, Germany

    P L Strissel, R Strick & S B Neumann

  3. Institut für Anatomie II, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    U Schumacher

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  1. A Kreisler
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Correspondence to P L Strissel.

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Kreisler, A., Strissel, P., Strick, R. et al. Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer. Oncogene 29, 5828–5838 (2010). https://doi.org/10.1038/onc.2010.321

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