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.

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

“…Other observations suggest a more complex role for ARID1A in tumorigenesis and some SWI/SNF components are oncogenic in certain contexts (Jubierre et al, 2016; Kadoch and Crabtree, 2013). In HCC, Zhao et.…”

Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities

“…Various SMARCA4 deficiencies manifest as tumor suppressor mechanisms [28,79], but a recent finding in neuroblastoma (NB) highlighted the ATPase as an oncogene [94]. Jubierre et al, showed overexpression of SMARCA4 in stage 4 NB patients was associated with worst outcomes [94].…”

“…Jubierre et al, showed overexpression of SMARCA4 in stage 4 NB patients was associated with worst outcomes [94]. Experiments both in cell culture and xenograft mouse models using a range of NB cell lines demonstrated apoptotic cell death upon shRNA-mediated knockdown of SMARCA4 [94].…”

Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming

“…Similarly, targeting BRM might be an effective strategy for targeting BRG1-deficient tumors (49, 50). As we and others have shown, BRG1 is upregulated but rarely mutated in primary breast and prostate tumors, in melanoma and neuroblastoma, and in pancreatic, gastric, and colorectal carcinomas (51–60). Mice heterozygous for Brg1 develop mammary tumors (61, 62).…”

“…For example, it is mutated in lung and other cancers. We and others have now shown that BRG1 is upregulated but rarely mutated in primary breast and prostate tumors, in melanoma and neuroblastoma, and in pancreatic, gastric, and colorectal carcinomas (51–60, 80). …”