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HDAC inhibition induces expression of scaffolding proteins critical for tumor progression in pediatric glioma: focus on EBP50 and IRSp53.
Capdevielle C
,
Desplat A
,
Charpentier J
,
Sagliocco F
,
Thiebaud P
,
Thézé N
,
Fédou S
,
Hooks KB
,
Silvestri R
,
Guyonnet-Duperat V
,
Petrel M
,
Raymond AA
,
Dupuy JW
,
Grosset CF
,
Hagedorn M
.
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BACKGROUND: Diffuse midline glioma (DMG) is a pediatric malignancy with poor prognosis. Most children die less than one year after diagnosis. Recently, mutations in histone H3 have been identified and are believed to be oncogenic drivers. Targeting this epigenetic abnormality using histone deacetylase (HDAC) inhibitors such as panobinostat (PS) is therefore a novel therapeutic option currently evaluated in clinical trials.
METHODS: BH3 profiling revealed engagement in an irreversible apoptotic process of glioma cells exposed to PS confirmed by annexin-V/propidium iodide staining. Using proteomic analysis of 3 DMG cell lines, we identified 2 proteins deregulated after PS treatment. We investigated biological effects of their downregulation by silencing RNA but also combinatory effects with PS treatment in vitro and in vivo using a chick embryoDMG model. Electron microscopy was used to validate protein localization.
RESULTS: Scaffolding proteins EBP50 and IRSp53 were upregulated by PS treatment. Reduction of these proteins in DMG cell lines leads to blockade of proliferation and migration, invasion, and an increase of apoptosis. EBP50 was found to be expressed in cytoplasm and nucleus in DMG cells, confirming known oncogenic locations of the protein. Treatment of glioma cells with PS together with genetic or chemical inhibition of EBP50 leads to more effective reduction of cell growth in vitro and in vivo.
CONCLUSION: Our data reveal a specific relation between HDAC inhibitors and scaffolding protein deregulation which might have a potential for therapeutic intervention for cancer treatment.
Ahmed,
I-BAR domains, IRSp53 and filopodium formation.
2010, Pubmed
Ahmed,
I-BAR domains, IRSp53 and filopodium formation.
2010,
Pubmed
Ballester,
Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas.
2013,
Pubmed
Deng,
BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents.
2007,
Pubmed
Dudakovic,
Histone deacetylase inhibition promotes osteoblast maturation by altering the histone H4 epigenome and reduces Akt phosphorylation.
2013,
Pubmed
Dudakovic,
Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells.
2015,
Pubmed
Dull,
A third-generation lentivirus vector with a conditional packaging system.
1998,
Pubmed
Funato,
IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness.
2004,
Pubmed
Garbett,
The tails of apical scaffolding proteins EBP50 and E3KARP regulate their localization and dynamics.
2013,
Pubmed
Goh,
mDia1 and WAVE2 proteins interact directly with IRSp53 in filopodia and are involved in filopodium formation.
2012,
Pubmed
Grasso,
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.
2015,
Pubmed
Grillo-Bosch,
Inhibition of PDZ domain-mediated interactions.
2013,
Pubmed
Hagedorn,
Accessing key steps of human tumor progression in vivo by using an avian embryo model.
2005,
Pubmed
Hayashi,
NHERF1/EBP50 is a new marker in colorectal cancer.
2010,
Pubmed
Hennika,
Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.
2017,
Pubmed
Henriet,
Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk.
2017,
Pubmed
Kislin,
NHERF-1: modulator of glioblastoma cell migration and invasion.
2009,
Pubmed
Louis,
The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.
2016,
Pubmed
Millard,
Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator with distinct filament bundling properties.
2007,
Pubmed
Mohler,
Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50.
1999,
Pubmed
Montero,
Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.
2015,
Pubmed
Mélard,
Molecular alterations and tumor suppressive function of the DUSP22 (Dual Specificity Phosphatase 22) gene in peripheral T-cell lymphoma subtypes.
2016,
Pubmed
Orr,
Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth.
2011,
Pubmed
Reczek,
Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family.
1997,
Pubmed
Richard,
Gene therapy of a mouse model of protoporphyria with a self-inactivating erythroid-specific lentiviral vector without preselection.
2001,
Pubmed
Salmon,
Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes.
2000,
Pubmed
Saponaro,
β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy.
2018,
Pubmed
Schroeder,
Gene profile analysis of osteoblast genes differentially regulated by histone deacetylase inhibitors.
2007,
Pubmed
Scita,
IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions.
2008,
Pubmed
Shiratsuchi,
Cloning and characterization of BAI-associated protein 1: a PDZ domain-containing protein that interacts with BAI1.
1998,
Pubmed
Truffaux,
Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma.
2015,
Pubmed
Vaquero,
Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology: from signaling regulation to clinical relevance.
2017,
Pubmed
Zhou,
Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma Treatment.
2017,
Pubmed
