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Epigenetic deregulation of GATA3 in neuroblastoma is associated with increased GATA3 protein expression and with poor outcomes

Abstract : To discover epigenetic changes that may underly neuroblastoma pathogenesis, we identified differentially methylated genes in neuroblastoma cells compared to neural crest cells, the presumptive precursors cells for neuroblastoma, by using genome-wide DNA methylation analysis. We previously described genes that were hypermethylated in neuroblastoma; in this paper we report on 67 hypomethylated genes, which were filtered to select genes that showed transcriptional over-expression and an association with poor prognosis in neuroblastoma, highlighting GATA3 for detailed studies. Specific methylation assays confirmed the hypomethylation of GATA3 in neuroblastoma, which correlated with high expression at both the RNA and protein level. Demethylation with azacytidine in cultured sympathetic ganglia cells led to increased GATA3 expression, suggesting a mechanistic link between GATA3 expression and DNA methylation. Neuroblastomas that had completely absent GATA3 methylation and/or very high levels of protein expression, were associated with poor prognosis. Knock-down of GATA3 in neuroblastoma cells lines inhibited cell proliferation and increased apoptosis but had no effect on cellular differentiation. These results identify GATA3 as an epigenetically regulated component of the neuroblastoma transcriptional control network, that is essential for neuroblastoma proliferation. This suggests that the GATA3 transcriptional network is a promising target for novel neuroblastoma therapies. Neuroblastoma (NB) is one of the commonest extra-cranial solid malignancies of childhood, which arises as a result of disordered development of the sympathetic nervous system from neural crest cells 1,2. Neuroblastoma is clinically heterogeneous, with younger patients (<18months) generally having localised tumours and good outcomes , whereas older children (>18months) mostly have disseminated tumours at diagnosis and poor outcomes 3. The clinical heterogeneity of neuroblastoma is reflected in its molecular pathogenesis, where no single pathway has been identified as being critical for tumour development. Oncogene activations were the first genetic alterations identified in neuroblastoma; initially MYCN amplification was identified in high-risk tumours 4 and later ALK mutations were discovered in inherited neuroblastoma and some sporadic high-risk tumours 5,6. Mutations in tumour suppressor genes such as PHOX2B 7 and NF1 8 have also been reported. Recent genome-wide analyses have identified genomic mutations and other alterations in chromatin remodelling genes such as ATRX, ARID1A and ARID1B, in components of the RAC-RHO pathway 9-11 and in TERT 12,13 , with relapsed tumours demonstrating an increased mutation rate 14,15. Like most childhood cancers, neuroblastomas contain fewer mutations than adult cancers 16,17 , with some tumours apparently containing no detectable driver mutations 9-11. In low-risk neuroblastomas, copy-number changes may drive tumorigenesis 18 , but the lack of driver mutations in many cases, emphasises the need to consider other mechanisms of pathogenesis, such as epigenetic alterations 19 .
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Bader Almutairi, Jessica Charlet, Anthony Dallosso, Marianna Szemes, Heather Etchevers, et al.. Epigenetic deregulation of GATA3 in neuroblastoma is associated with increased GATA3 protein expression and with poor outcomes. Scientific Reports, Nature Publishing Group, 2019, pp.18934. ⟨10.1038/s41598-019-55382-6⟩. ⟨hal-02407665⟩

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