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, 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.

The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation

“…PFI-3 treatment increased the accessibility of an mSWI/SNF-repressed promoter and its gene expression(90). In these and other studies, PFI-3 altered both gene expression patterns dependent on mSWI/SNF bromodomaincontaining proteins and the cellular and organismal phenotypes controlled by those genes(87,88,(91)(92)(93)(94)(95)(96). The data indicate that the pleiotropic effects of PFI-3 and inhibition of mSWI/SNF bromodomains links to the ability of the chromatin remodeling enzyme to modulate gene expression.In the realm of tissue specification, PFI-3 treatment caused a loss of "stemness" and promoted differentiation of ESCs and trophoblast and neural stem cells in the absence of differentiation signaling(41,97).…”

Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3

“…In our previous report, we described the ability of an miR-10b antagonist (antimiR-10b) conjugated to Gint4.T or GL21.T aptamers to selectively target miR-10b and inhibit GSC stem-like phenotype and tumour sphere formation [ 24 ]. miR-10b is a biomarker that is highly expressed in GBM and GSCs, acting as an oncomiR to promote cancer stem cell propagation [ 8 , 22 ]. Although, STAT3 and miR-10b contribute to overlapping regulatory pathways, there is no evidence of direct expression regulation.…”

“…STAT3 abnormal activation has been reported to be involved in the progression of several cancer types, including GBM [ 12 , 13 , 14 , 15 , 16 ]. In addition, its inhibition resulted in an effective alteration of GSC sphere formation and stem-like growth potential [ 17 , 18 , 19 ], and the pathway has been showed to play a crucial role in GSC chemo and radio-resistance [ 20 , 21 , 22 ]. These studies indicate STAT3 as a highly promising therapeutic target for GBM able to affect both bulk tumour cells and resistant GSCs, enhancing the success of the treatment.…”

APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade

“…To determine APELA protein expression in GBM patient specimens, we performed IHC on sections cut from FFPE tissue blocks of GBM patients and normal brain tissue. Since Nestin is a stem cell marker expressed in BTICs [16,17], we also determined whether APELA-expressing cells could be identified in a putative stem cell niche of Nestin-expressing cells by IHC using an anti-Nestin and anti-APELA specific antiserum. As shown in Figure 3 (lower three panels), Nestin staining was observed in a cluster of cells in three different GBM tumor samples that also showed APELA staining.…”