Achaete-Scute Homolog 1 Expression Controls Cellular Differentiation of Neuroblastoma

Abstract

Neuroblastoma, the major cause of infant cancer deaths, results from fast proliferation of undifferentiated neuroblasts. Treatment of high-risk neuroblastoma includes differentiation with retinoic acid (RA); however, the resistance of many of these tumors to RA-induced differentiation poses a considerable challenge. Human achaete-scute homolog 1 (hASH1) is a proneural basic helix-loop-helix transcription factor essential for neurogenesis and is often upregulated in neuroblastoma. Here, we identified a novel function for hASH1 in regulating the differentiation phenotype of neuroblastoma cells. Global analysis of 986 human neuroblastoma datasets revealed a negative correlation between hASH1 and neuron differentiation that was independent of the N-myc (MYCN) oncogene. Using RA to induce neuron differentiation in two neuroblastoma cell lines displaying high and low levels of hASH1 expression, we confirmed the link between hASH1 expression and the differentiation defective phenotype, which was reversed by silencing hASH1 or by hypoxic preconditioning. We further show that hASH1 suppresses neuronal differentiation by inhibiting transcription at the RA receptor element. Collectively, our data indicate hASH1 to be key for understanding neuroblastoma resistance to differentiation therapy and pave the way for hASH1-targeted therapies for augmenting the response of neuroblastoma to differentiation therapy.

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

“…Among the most affected functions were differentiation pathways, including neuronal differentiation and neuritogenesis (tables S5 and S6). Some prominent changes among differentiation genes included the critical differentiation genes enolase 2 (neuron-specific enolase, ENO2 ) (25), chromodomain helicase DNA binding protein 5 ( CHD5 ) (26), nerve growth factor ( NGF ) (26), and neuregulin 1 ( NRG1 ) (27), which were up-regulated, whereas the differentiation blockers, achaete-scute homolog 1 ( ASCL1 ) (28, 29) and MYCN (2), were reduced (Fig. 2B).…”

The developmental origin of brain tumours: a cellular and molecular framework

“…In the future, it will be important to explore the integration of ERK and CDK-mediated ASCL1 phosphoregulation in glioma initiation and maintenance, and to explore whether inhibition of ASCL1 phosphorylation is a rational strategy with which to decrease tumourigenicity by potentiating glioma stem cell differentiation. In addition to a role in brain cancer biology, ASCL1 is expressed in various neuroendocrine tumours of the lung ( Borromeo et al, 2016 ; Jiang et al, 2009 ), prostate and intestine, and in neuroblastoma ( Isogai et al, 2011 ; Kasim et al, 2016 ; Wylie et al, 2015 ), indicating a potentially more widespread role in tumourigenesis (see Table 2 ).…”

The untold stories of the speech gene, the FOXP2 cancer gene

“…In these studies, genes were selected to investigate the role of FOXP2 in language and neurodevelopment and were mostly assessed in neuronal cell models. We analyzed these genes with Ingenuity Pathway Analysis software: thirty-three of them were involved in tumorigenesis of carcinoma, with high levels of ASCL1 and MET in neuroblastoma formation [ 115 - 117 ], and PTCH1 in medulloblastoma initiation [ 118 ]. Moreover, these genes were also involved in the oncogenic progression of primitive neuroectodermal tumor in IPA analysis.…”