Chromatin remodeling factor BRG1 regulates stemness and chemosensitivity of glioma initiating cells
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ABSTRACT:
PROVIDER: PRJNA478991 | ENA |
REPOSITORIES: ENA
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Project description: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.
2018-07-03 | GSE116545 | GEO
Project description:Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is refractory to existing therapeutic regimens, which reflects 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 BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, plays a fundamental role in maintaining GICs in their stem-like state. In addition, we identified a novel mechanism by which BRG1 regulates glycolysis genes critical for GICs. BRG1 downregulates the expression of TXNIP, a negative regulator of glycolysis. BRG1 knockdown also triggered the STAT3 pathway, which led to TXNIP activation. We further identified that TXNIP is an STAT3-regulated gene. Moreover, BRG1 suppressed the expression of interferon-stimulated genes, which are negatively regulated by STAT3 and regulate tumorigenesis. We further 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 inhibiting 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 in GIC stemness and chemosensitivity will inform the development of better targeted therapies in GBM and possibly other cancers. Stem Cells 2018;36:1806-12.
| S-EPMC7427091 | biostudies-literature
Project description:To identify factors involved in tumorigenicity of glioma-initiating cells (GICs), we compared gene expression in GIC-like cells with and without sox11 expression. We established sox11-expressing mouse glioma-initiating cell (GIC)-like cell line (NSCL61s), NSCL61s-sox11, which lost tumorigenicity when transplanted in vivo. We think that genes, which are differently expressed between NSCL61s and NSCL61s-sox11, would be new targets for glioma therapy.
2009-11-30 | E-GEOD-17076 | biostudies-arrayexpress
Project description:To identify factors involved in glioma-initiating cells (GICs), we compared gene expressions between GIC-like cells and non-GICs.
2011-06-01 | GSE28091 | GEO
Project description:To identify a novel miRNA that is aberrantly expressed in GICs, we analyzed differences in miRNA expression between the mouse GICs, NSCL61 and OPCL61, showing characteristic features of cancer stem cell, and their parental cells by miRNA microarrays. neural stem cells, glioma-initiating cells (GICs) from neural stem cells, oligodendrocyte precursor cells, glioma-initiating cells (GICs) from oligodendrocyte precursor cells.
2015-04-07 | E-GEOD-61080 | biostudies-arrayexpress
Project description:To identify factors involved in tumorigenicity of glioma-initiating cells (GICs), we compared gene expression in GIC-like cells with and without sox11 expression.
2009-12-01 | GSE17076 | GEO
Project description:To identify factors involved in glioma-initiating cells (GICs), we compared gene expression between GIC-like cells and non-GICs.
2009-12-01 | GSE17062 | GEO
Project description:To identify factors involved in glioma-initiating cells (GICs), we compared gene expressions between GIC-like cells and non-GICs. p53-deficient Neural stem cells (NSCs), oligodendrocyte precursor cells (OPCs), and astrocytes (ASTs) were transfected with pCMS-EGFP-HRasL61 and pBabe-neo by electroporation and cultured in 0.5 mg/ml neomycin. The GFP-positive stable NSCs (NSCL61s), OPCs (OPCL61s) and ASTs (ASTL61s) were purified by flow cytometry. Total RNA was prepared using a RNeasy Mini Kit (QIAGEN) and used for the expression analysis.
2011-06-01 | E-GEOD-28091 | biostudies-arrayexpress
Project description:Glioma initiating/stem cells (GIC/GSC) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC/GSC maintenance/differentiation, we established GIC/GSC clones, having the potential to differentiate into malignant gliomas, from glioblastoma patient’s tissues, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart (iPEACH). The data integration and extraction of global proteins and mRNAs revealed that, during the GIC/GSC differentiation, cell adhesion molecules including integrin aV/ECMs and RAS-MAPK/PI3K signalings were significantly up-regulated, meanwhile, SOX2, CD133, and specific proteoglycans/synthetic-enzymes/metabolic pathways were obviously down-regulated. Among them, we focused proteoglycans and their synthetic-enzymes. GIC/GSC differentiation was significantly associated with the decrease of CSPG (CS-modified form) and dramatically induced by the CS-degradation enzyme which also induces the up-regulation of ERK-AKT signaling and GFAP without any other agents. Importantly, these differentiation processes were also associated with the interaction of CSPG (CS-unmodified form) and integrin-aV, and suppressed by integrin-inhibitors/CS administrations significantly. Combination treatments of a cancer-drug Temozolomide and these GIC/GSC-differentiation inhibitors suppressed glioma progression, increased the chemosensitivities, and led the longer survival of mouse xenograft-models. Functional integrated proteomics for the first time demonstrates that the GIC/GSC induces the specific proteoglycans to regulate GIC/GSC stemness/differentiation via the integlin signalings which may be a clinical target against malignant gliomas.
2018-11-30 | PXD008331 | JPOST Repository
Project description:Glioma initiating/stem cells (GIC/GSC) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC/GSC maintenance/differentiation, we established GIC/GSC clones, having the potential to differentiate into malignant gliomas, from glioblastoma patient’s tissues, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart (iPEACH). The data integration and extraction of global proteins and mRNAs revealed that, during the GIC/GSC differentiation, cell adhesion molecules including integrin aV/ECMs and RAS-MAPK/PI3K signalings were significantly up-regulated, meanwhile, SOX2, CD133, and specific proteoglycans/synthetic-enzymes/metabolic pathways were obviously down-regulated. Among them, we focused proteoglycans and their synthetic-enzymes. GIC/GSC differentiation was significantly associated with the decrease of CSPG (CS-modified form) and dramatically induced by the CS-degradation enzyme which also induces the up-regulation of ERK-AKT signaling and GFAP without any other agents. Importantly, these differentiation processes were also associated with the interaction of CSPG (CS-unmodified form) and integrin-aV, and suppressed by integrin-inhibitors/CS administrations significantly. Combination treatments of a cancer-drug Temozolomide and these GIC/GSC-differentiation inhibitors suppressed glioma progression, increased the chemosensitivities, and led the longer survival of mouse xenograft-models. Functional integrated proteomics for the first time demonstrates that the GIC/GSC induces the specific proteoglycans to regulate GIC/GSC stemness/differentiation via the integlin signalings which may be a clinical target against malignant gliomas.
2018-11-30 | PXD008332 | JPOST Repository