Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Target Concepts:
Gene/Protein
Disease
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Query: UMLS:C0017636 (
glioblastoma
)
18,345
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Glioblastomas
exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived
glioblastoma
stem cells (GSCs) express high levels of
Achaete-scute homolog 1
(
ASCL1
), a proneural transcription factor involved in normal neurogenesis.
ASCL1
hi
GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas
ASCL1
lo
GSCs do not. Increasing
ASCL1
levels in
ASCL1
lo
GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity.
ASCL1
mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.
...
PMID:ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells. 2888 68
Achaete-scute homolog 1
gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of
glioblastoma
(
GBM
) that has a relevant role in the neuronal-like differentiation of
GBM
cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating
GBM
differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in
GBM
; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of
GBM
belonging to the MES subgroup.
...
PMID:The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1. 3053 87
