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FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins

Oncogene volume 21, pages 6264–6277 (2002)Cite this article

Abstract

The related members of the interleukin-6 (IL-6) family of cytokines, leukemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6 are inflammatory mediators that control differentiated cell functions as well as proliferation. The cellular responsiveness to these cytokines is largely determined by the expression of the appropriate receptor proteins. The receptor expression profile for each cell type is established during differentiation and is often altered during oncogenic transformation. Since inhibition of histone deacetylases (HDAC) has the potential to re-activate epigenetically silenced genes, we asked whether inhibition of HDAC enhances the expression of IL-6 cytokine receptors and, thus, increase desirable cytokine responses. We demonstrate that treatment with FR901228 (FR), an HDAC inhibitor, increases the responsiveness to LIF in different cell types, including normal fibroblasts, epithelial cells, macrophages and splenocytes, as well as various tumor cell lines. Depending on the cell type, FR treatment also enhances the responsiveness to OSM and IL-6. These effects involve a transcriptional induction of the cytokine receptor subunits LIFRα, OSMRβ, gp130, or the transcription factor STAT3. FR-specific induction of LIFRα occurs independently of de novo protein synthesis and cell proliferation and is mediated in part by the CBP/p300 coactivator. Chromatin immunoprecipitation experiments indicate that the expression of LIFRα and gp130 genes correlates with the level of acetylated histone 3 associated with the receptor promoter regions. The FR-stimulated expression of IL-6-type cytokine receptors in certain tumor cells also provided improved conditions for suppression of cell growth by taking advantage of the growth inhibitory effect of these cytokines.

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Acknowledgements

We are grateful to Immunex Corporation and Wyeth Research (formally Genetics Institute) for generously providing cytokines, Dr ML Avantaggiati, for the expression vectors of p300, Dr G Loewen for bronchial brushings, Dr M Wetzler for leukemia and lymphoma cells, and Dr G Bepler for lung cancer cells. This work was supported by NIH grants CA 85580 and DK 38866 to H Baumann, CA 68612 to WA Held, and Roswell Park Grant CA16056. F Blanchard is a recipient of a fellowship from the Association pour la Recherche contre le Cancer (ARC).

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  1. Frédéric Blanchard

    Present address: INSERM U463, Institut de Biologie, 9 Quai Moncousu, Nantes, Cedex 01, 44035, France

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, 14263, New York, NY, USA

    Frédéric Blanchard, Erin Kinzie, Yanping Wang, William A Held & Heinz Baumann

  2. Division of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, 14263, New York, NY, USA

    Bonnie B Asch

  3. INSERM U463, Institut de Biologie, 9 Quai Moncousu, Nantes, Cedex 01, 44035, France

    Laurence Duplomb & Anne Godard

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  1. Frédéric Blanchard
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Correspondence to Frédéric Blanchard or Heinz Baumann.

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Blanchard, F., Kinzie, E., Wang, Y. et al. FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. Oncogene 21, 6264–6277 (2002). https://doi.org/10.1038/sj.onc.1205777

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