Chromatin remodeling factor BRG1 regulates stemness and chemosensitivity of glioma initiating cells

ABSTRACT: Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is refractory to existing therapeutic regimens due in part to the presence of stem-like cells, termed Glioma-Initiating Cells (GICs). The complex interactions between different signaling pathways and epigenetic regulation of key genes may be critical in the maintaining GICs in their stem-like state. Although several signaling pathways have been identified as being dysregulated in GBM, the prognosis of GBM patients remains miserable despite improvements in targeted therapies. In this report we identified that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex plays a fundamental role in the maintaining GICs in their stem-like state. In addition, we identified a novel mechanism by which BRG1 maintains glucose levels critical for GICs. BRG1 downregulates the expression of TXNIP, a negative regulator of glycolysis. BRG1 knockdown led to STAT3 upregulation, which in turn led to TXNIP activation. We further identified that TXNIP is a STAT3-regulated gene. Moreover, BRG1 suppressed the expression of interferon-stimulated genes, which regulate tumorigenesis. We also demonstrate that BRG1 plays a critical role in the drug resistance of GICs and in GIC-induced tumorigenesis. By genetic and pharmacological means, we found that inhibition of BRG1 can sensitize GICs to chemotherapeutic drugs, temozolomide and Carmustine. Our studies suggest that BRG1 may be a novel therapeutic target in GBM. The identification of the critical role that BRG1 plays GIC stemness and chemosensitivity in GICs will inform the development of better targeted therapies in GBM and possibly other cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116545 | GEO | 2018/07/03

REPOSITORIES: GEO