Neuroblastoma (NB) is a neoplasm of the sympathetic nervous system, and is the most common solid tumor of infancy. NBs are very heterogeneous, with a clinical course ranging from spontaneous regression to resistance to all current forms of treatment. High-risk patients need intense chemotherapy, and only 30–40% will be cured. Relapsed or metastatic tumors acquire multi-drug resistance, raising the need for alternative treatments. Owing to the diverse mechanisms that are responsible of NB chemoresistance, we aimed to target epigenetic factors that control multiple pathways to bypass therapy resistance. We found that the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4/BRG1) was consistently upregulated in advanced stages of NB, with high BRG1 levels being indicative of poor outcome. Loss-of-function experiments in vitro and in vivo showed that BRG1 is essential for the proliferation of NB cells. Furthermore, whole-genome transcriptome analysis revealed that BRG1 controls the expression of key elements of oncogenic pathways such as PI3K/AKT and BCL2, which offers a promising new combination therapy for high-risk NB.
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bromodomain and extraterminal domain
V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog
quantitative real-time PCR
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We thank members of the Genomics Facility, Statitstics and Bioinformatic Unit, Pathology Laboratory and the Animal Core Facilities of the Vall d’Hebron Research Institute. We thank Dr Mireia Duñac, Dr Jose R Bayascas and Dr Diego Arango for precious advice. We thank Ms Christine O’Hara for text correction. This work was supported by the Instituto de Salud Carlos III (CP11/00052, RD12/0036/0016, RD12/0036/0020, RD12/0036/0045, RD12/0036/0012) co-financed by the European Regional Development Fund (ERDF), Generalitat de Catalunya 2014-SGR-660 and Marie Curie Career Integration Grants.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Jubierre, L., Soriano, A., Planells-Ferrer, L. et al. BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways. Oncogene 35, 5179–5190 (2016) doi:10.1038/onc.2016.50
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