title: BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways.
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.
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Jubierre
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Cell Signaling and Apoptosis Group, VHIR-UAB, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Planells-Ferrer
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: París-Coderch
authors.affiliation: Vall d'Hebron Institut of Oncology (VHIO), Stem Cell and Cancer Laboratory, Barcelona, Spain.
authors.forename: S P
authors.initials: SP
authors.lastname: Tenbaum
authors.affiliation: Epigenetic and Cancer Biology Program-PEBC/Bellvitge Biomedical Research Institute-IDIBELL Barcelona, Barcelona, Spain.
authors.forename: O A
authors.initials: OA
authors.lastname: Romero
authors.affiliation: Cell Signaling and Apoptosis Group, VHIR-UAB, Barcelona, Spain.
authors.forename: R S
authors.initials: RS
authors.lastname: Moubarak
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Almazán-Moga
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Molist
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Roma
authors.affiliation: School of Medicine, University of Valencia, Valencia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Navarro
authors.affiliation: School of Medicine, University of Valencia, Valencia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Noguera
authors.affiliation: Cell Signaling and Apoptosis Group, VHIR-UAB, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Sánchez-Céspedes
authors.affiliation: Cell Signaling and Apoptosis Group, VHIR-UAB, Barcelona, Spain.
authors.forename: J X
authors.initials: JX
authors.lastname: Comella
authors.affiliation: Vall d'Hebron Institut of Oncology (VHIO), Stem Cell and Cancer Laboratory, Barcelona, Spain.
authors.forename: H G
authors.initials: HG
authors.lastname: Palmer
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Sánchez de Toledo
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Gallego
authors.affiliation: Laboratory of Translational Research in Child and Adolescent Cancer. Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Segura
mesh_terms: D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; C084108:SMARCA4 protein, human; D004265:DNA Helicases