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HDAC7 inhibition resets STAT3 tumorigenic activity in human glioblastoma independently of EGFR and PTEN: new opportunities for selected targeted therapies

Oncogene volume 35, pages 4481–4494 (2016)Cite this article

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Abstract

To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53. Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo. In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.

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Acknowledgements

The authors acknowledge the experimental support of Dr Chantal Humblet and Ms Alice Marquet (GIGA-histology platform, ULg), Dr Sandra Ormenese (GIGA-imaging platform, ULg) as well as of Evgenia Turtoi (Metastasis Research Laboratory) for the immunohistochemistry analysis and of Naima Maloujahmoum (Metastasis Research Laboratory) for the cell culture. The authors are also thankful to Dr Stephanie Gofflot from the institutional Biobank of the University Hospital Liege for providing GBM fresh tissues and to Dr Gilles Doumont (group of Prof Serge Goldman, Université libre de Bruxelles) for help with animal experiments. The authors are grateful to Ms. Ana Turtoi for proofreading the manuscript. The results shown in this work are in part based on data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported with grants from the University of Liège (Concerted Research Action Program (IDEA project)) and from the National Fund for Scientific Research (FNRS/TELEVIE). Andrei Turtoi is a post-doctoral research fellow (FNRS/TELEVIE) and Akeila Bellahcène is a senior research associate (FNRS). Arnaud Blomme is a post-doctoral research fellow (FNRS/TELEVIE). The Center for Microscopy and Molecular Imaging (CMMI) is supported by the European Regional Development Fund and Wallonia. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. P Peixoto, A Blomme and B Costanza: Co-first authors.

Authors and Affiliations

  1. Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium

    P Peixoto, A Blomme, B Costanza, A P Palacios, O Peulen, P Maris, V Hennequière, A Henry, A Bellahcène, V Castronovo & A Turtoi

  2. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    R Ronca & S Rezzola

  3. Department of Radiology, University Hospital Liège, Liège, Belgium

    L Schoysman & P Meunier

  4. Department of General, NMR and Molecular Imaging Laboratory, Organic and Biomedical Chemistry, University of Mons, Mons, Belgium

    S Boutry & R N Muller

  5. Center for Microscopy and Molecular Imaging, Charleroi, Belgium

    S Boutry & R N Muller

  6. GIGA Neurosciences, University of Liège, Liège, Belgium

    N Goffart & B Rogister

  7. GIGA-Viral Vectors Platform, University of Liège, Liège, Belgium

    E Di Valentin

  8. Department of Pathology, University Hospital Liège, Liège, Belgium

    E Bianchi & P Delvenne

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Peixoto, P., Blomme, A., Costanza, B. et al. HDAC7 inhibition resets STAT3 tumorigenic activity in human glioblastoma independently of EGFR and PTEN: new opportunities for selected targeted therapies. Oncogene 35, 4481–4494 (2016). https://doi.org/10.1038/onc.2015.506

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