Original Article | Published:

BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways

Oncogene volume 35, pages 51795190 (29 September 2016) | Download Citation

Abstract

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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Acknowledgements

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.

Author information

Affiliations

  1. Laboratory of Translational Research in Child and Adolescent Cancer. Vall d’Hebron Research Institute (VHIR)-UAB, Barcelona, Spain

    • L Jubierre
    • , A Soriano
    • , L París-Coderch
    • , A Almazán-Moga
    • , C Molist
    • , J Roma
    • , J Sánchez de Toledo
    • , S Gallego
    •  & M F Segura
  2. Cell Signaling and Apoptosis Group, VHIR-UAB, Barcelona, Spain

    • L Planells-Ferrer
    • , R S Moubarak
    • , M Sánchez-Céspedes
    •  & J X Comella
  3. Vall d’Hebron Institut of Oncology (VHIO), Stem Cell and Cancer Laboratory, Barcelona, Spain

    • S P Tenbaum
    •  & H G Palmer
  4. Epigenetic and Cancer Biology Program-PEBC/Bellvitge Biomedical Research Institute-IDIBELL Barcelona, Barcelona, Spain

    • O A Romero
  5. School of Medicine, University of Valencia, Valencia, Spain

    • S Navarro
    •  & R Noguera

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The authors declare no conflict of interest.

Corresponding author

Correspondence to M F Segura.

Supplementary information

Glossary

BET

bromodomain and extraterminal domain

MYCN

V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog

NB

neuroblastoma

NSC

non-silencing control

PI3K

phosphatidylinositol-4,5-bisphosphate 3-kinase

qPCR

quantitative real-time PCR

SWI/SNF

SWItch/Sucrose NonFermentable.

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DOI

https://doi.org/10.1038/onc.2016.50

Supplementary Information accompanies this paper on the Oncogene website (http://www.nature.com/onc)

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