The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1

Ashwin Narayanan, Filippo Gagliardi, Alberto L. Gallotti, Stefania Mazzoleni, Manuela Cominelli, Luca Fagnocchi, Mauro Pala, Ignazio S. Piras, Paola Zordan, Nicole Moretta, Elisa Tratta, Gianluca Brugnara, Luisa Altabella, Giuseppina Bozzuto, Petra Gorombei, Agnese Molinari, Rose Ann Padua, Alessandro Bulfone, Letterio S. Politi, Andrea FaliniAntonella Castellano, Pietro Mortini, Alessio Zippo, Pietro L. Poliani, Rossella Galli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Narayanan, A., Gagliardi, F., Gallotti, A. L., Mazzoleni, S., Cominelli, M., Fagnocchi, L., Pala, M., Piras, I. S., Zordan, P., Moretta, N., Tratta, E., Brugnara, G., Altabella, L., Bozzuto, G., Gorombei, P., Molinari, A., Padua, R. A., Bulfone, A., Politi, L. S., ... Galli, R. (Accepted/In press). The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1. Cell Death and Differentiation. https://doi.org/10.1038/s41418-018-0248-7