title: Small-molecule blocks malignant astrocyte proliferation and induces neuronal gene expression.
abstract: In the central nervous system (CNS), neural stem cells (NSCs) differentiate into neurons, astrocytes, and oligodendrocytes--these cell lineages are considered unidirectional and irreversible under normal conditions. The introduction of a defined set of transcription factors has been shown to directly convert terminally differentiated cells into pluripotent stem cells, reinforcing the notion that preserving cellular identity is an active process. Indeed, recent studies highlight that tumor suppressor genes (TSGs) such as Ink4a/Arf and p53, control the barrier to efficient reprogramming, leaving open the question whether the same TSGs function to maintain the differentiated state. During malignancy or following brain injury, mature astrocytes have been reported to re-express neuronal genes and re-gain neurogenic potential to a certain degree, yet few studies have addressed the underlying mechanisms due to a limited number of cellular models or tools to probe this process. Here, we use a synthetic small-molecule (isoxazole) to demonstrate that highly malignant EGFRvIII-expressing Ink4a/Arf(-/-); Pten(-/-) astrocytes downregulated their astrocyte character, re-entered the cell cycle, and upregulated neuronal gene expression. As a collateral discovery, isoxazole small-molecules blocked tumor cell proliferation in vitro, a phenotype likely coupled to activation of neuronal gene expression. Similarly, histone deacetylase inhibitors induced neuronal gene expression and morphologic changes associated with the neuronal phenotype, suggesting the involvement of epigenetic-mediated gene activation. Our study assesses the contribution of specific genetic pathways underlying the de-differentiation potential of astrocytes and uncovers a novel pharmacological tool to explore astrocyte plasticity, which may bring insight to reprogramming and anti-tumor strategies.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hsu
authors.forename: Hector R
authors.initials: HR
authors.lastname: Aguilar
authors.forename: Doug E
authors.initials: DE
authors.lastname: Frantz
authors.forename: Jay W
authors.initials: JW
authors.lastname: Schneider
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bachoo
authors.forename: Jenny
authors.initials: J
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology*; D054337:Cell Dedifferentiation / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D007555:Isoxazoles; C560085:N-cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide; D013876:Thiophenes; D025521:Tumor Suppressor Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors