title: HDAC7 inhibition resets STAT3 tumorigenic activity in human glioblastoma independently of EGFR and PTEN: new opportunities for selected targeted therapies.
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.
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: P
authors: P
authors: Peixoto
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Blomme
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: B
authors: B
authors: Costanza
authors: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors: R
authors: R
authors: Ronca
authors: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors: S
authors: S
authors: Rezzola
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: A P
authors: AP
authors: Palacios
authors: Department of Radiology, University Hospital Liège, Liège, Belgium.
authors: L
authors: L
authors: Schoysman
authors: NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Mons, Belgium.|Center for Microscopy and Molecular Imaging, Charleroi, Belgium.
authors: S
authors: S
authors: Boutry
authors: GIGA Neurosciences, University of Liège, Liège, Belgium.
authors: N
authors: N
authors: Goffart
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: O
authors: O
authors: Peulen
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: P
authors: P
authors: Maris
authors: GIGA-Viral Vectors Platform, University of Liège, Liège, Belgium.
authors: E
authors: E
authors: Di Valentin
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: V
authors: V
authors: Hennequière
authors: Department of Pathology, University Hospital Liège, Liège, Belgium.
authors: E
authors: E
authors: Bianchi
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Henry
authors: Department of Radiology, University Hospital Liège, Liège, Belgium.
authors: P
authors: P
authors: Meunier
authors: GIGA Neurosciences, University of Liège, Liège, Belgium.
authors: B
authors: B
authors: Rogister
authors: NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Mons, Belgium.|Center for Microscopy and Molecular Imaging, Charleroi, Belgium.
authors: R N
authors: RN
authors: Muller
authors: Department of Pathology, University Hospital Liège, Liège, Belgium.
authors: P
authors: P
authors: Delvenne
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Bellahcène
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: V
authors: V
authors: Castronovo
authors: Metastasis Research Laboratory, GIGA Cancer, Avenue d'Hopital 3, University of Liège, Liège, Belgium.
authors: A
authors: A
authors: Turtoi
mesh_terms: D054758:A Kinase Anchor Proteins / Q000502:physiology; D000818:Animals; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000502:physiology*; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000032:analysis / Q000502:physiology*; D006801:Humans; D053613:Janus Kinase 1 / Q000502:physiology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000502:physiology*
chemical_list: D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C543273:HDAC7 protein, human; D006655:Histone Deacetylases