Abstract
Glioma stem cells (GSC) play a major role in drug resistance and tumor recurrence. Using a genetic screen with a set of shRNAs that can target chromatin regulators in a GSC model, we have HDAC3 as a major negative regulator of GSC differentiation. Inhibition of HDAC3 using a pharmacological inhibitor or a siRNA led to the induction of GSC differentiation into astrocytes. Consequently, HDAC3-inhibition also caused a strong reduction of tumor-promoting and self-renewal capabilities of GSCs. These phenotypes were highly associated with an increased acetylation of SMAD7, which protected its ubiquitination. SMAD7 inhibits a TGF-β signaling axis that is required for maintaining stemness. These results demonstrate that HDAC3 appears to be a proper target in anti-glioma therapy.
Keywords:
Differentiation; Glioma stem cells; Growth arrest; HDAC3; SMAD7; TGF-β.
Copyright © 2020. Published by Elsevier Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / pharmacology*
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Animals
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Differentiation / drug effects*
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Transformation, Neoplastic / drug effects
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Glioma / metabolism
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Glioma / pathology
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / pathology
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Phenylenediamines / pharmacology*
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RNA, Small Interfering / genetics
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Signal Transduction
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Smad7 Protein / metabolism*
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Transforming Growth Factor beta / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Acrylamides
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Histone Deacetylase Inhibitors
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Phenylenediamines
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RGFP966
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RNA, Small Interfering
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SMAD7 protein, human
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Smad7 Protein
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Transforming Growth Factor beta
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Histone Deacetylases
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histone deacetylase 3