Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

Marquez-Vilendrer, Stefanie B; Kumar, Sudhir; Gramling, Sarah; Lü, Li; Reisman, David

doi:10.18632/oncoscience.323

Cited by 26 publications

(32 citation statements)

References 43 publications

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“…Although BRG1‐KD in ESCs and in GICs has been reported to reduce proliferation , BRG1 loss also has been shown to increase the proliferation of some cell lines . Consistent with the latter reports, we found that BRG1‐KD enhanced proliferation of both GBM6 and X16 GICs.…”

Section: Discussionsupporting

confidence: 91%

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 91%

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

et al. 2018

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“…In these cases, BRM loss occurs because of epigenetic silencing of SMARCA2 locus, 30,39 and the resultant BRM loss has been demonstrated to paradoxically potentiate epithelial to mesenchymal transition and sarcomatoid transformation. 9,36 Interestingly, Rekhtman et al 18 recently described 2 BRG1-deficient tumors with sharply delineated sarcomatoid areas wherein only the sarcomatoid areas showed loss of BRM, supporting this hypothesis. Epigenetic repression of SMARCA2 appears to be reversible with EZH2 inhibitors, and SMARCA4mutant NSCLC cell lines with decreased SMARCA2 mRNA and BRM loss show a fall in proliferative activity when treated with EZH2 inhibitors.…”

Section: Discussionmentioning

confidence: 90%

“…28 BRG1 loss appears to result in failure of ATPasedependent eviction of polycomb recessive complexes, leading to widespread chromatin reorganization and changes in the expression levels of many genes implicated in the etiology of NSCLC. [34][35][36] In mouse models, heterozygous SMARCA4-knockout mice develop lung adenomas, suggesting that loss of even one SMARCA4 allele is sufficient for tumor initiation. 30 Biallelic SMARCA4 knockout, however, causes apoptosis of normal lung cells and loss of cell viability.…”

Section: Discussionmentioning

confidence: 99%

SMARCA4/BRG1–Deficient Non–Small Cell Lung Carcinomas: A Case Series and Review of the Literature

Nambirajan

Singh

Bhardwaj

et al. 2020

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Somatic mutations in SMARCA4 (SWI/SNF–related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or BRG1 (Brahma-related gene 1) loss identifies a subset of non–small cell lung carcinomas (NSCLCs) lacking alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes. Preliminary observations suggest responsiveness to immunotherapy and targeted therapies. Objective.— To study BRG1 loss in NSCLCs and elucidate the clinicopathologic profile of such SMARCA4-deficient NSCLCs. Design.— Non–small cell lung carcinomas diagnosed during 6 years were subject to immunohistochemistry for BRG1 and BRM (Brahma). Tumors with BRG1 loss were stained with antibodies against thyroid transcription factor 1 (TTF-1), p40, cytokeratins, hepatocyte paraffin 1 (Hep Par 1), Sal-like protein 4 (SALL4), CD34, SRY-box 2 (SOX2), chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1. EGFR mutation testing was performed by polymerase chain reaction–based method. Results.— Among 100 NSCLCs tested, 4 cases (4%) showed BRG1 loss. The histology ranged from solid adenocarcinomas (n = 1) to large cell/poorly differentiated carcinomas (n = 3) with clear cell cytology in 2 cases. All showed loss/reduction of BRM with variable cytokeratin and SALL4 expression, and were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations. CD34 and SOX2 were negative in all 4 cases. Isolated BRM loss was common (21%), distributed across all NSCLC subtypes including squamous cell carcinomas and a hepatoid adenocarcinoma. Conclusions.— BRG1 loss occurs in a subset of TTF-1/p40–negative poorly differentiated NSCLCs. Identification and follow-up will clarify the prognosis, diagnostic criteria, and potential for therapeutic personalization.

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“…Known chromatin remodelers with functional roles in EMT ( Figure 5) have been reviewed see (174) and include the NuRD subunits MTA1 and MTA3 within the CHD family, the BPTF subunit of the ISWI family member NURF (116), and the BAF250/ARID1, BRG1, and hBRM subunits of the mammalian SWI/SNF complex (174,175). Interestingly, the combined loss of BAF250A/ARID1A and gain of expressed mutated PI3K subunit PIK3CA H1047R results in partial EMT in the endometrial epithelium (176).…”

Section: Remodeling Our Understanding Of Chromatin Machinery In Emtmentioning

confidence: 99%

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

Lavin

Tiwari

2020

Front. Oncol.

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Epithelial to mesenchymal transition (EMT) is the process whereby a polarized epithelial cell ceases to maintain cell-cell contacts, loses expression of characteristic epithelial cell markers, and acquires mesenchymal cell markers and properties such as motility, contractile ability, and invasiveness. A complex process that occurs during development and many disease states, EMT involves a plethora of transcription factors (TFs) and signaling pathways. Whilst great advances have been made in both our understanding of the progressive cell-fate changes during EMT and the gene regulatory networks that drive this process, there are still gaps in our knowledge. Epigenetic modifications are dynamic, chromatin modifying enzymes are vast and varied, transcription factors are pleiotropic, and signaling pathways are multifaceted and rarely act alone. Therefore, it is of great importance that we decipher and understand each intricate step of the process and how these players at different levels crosstalk with each other to successfully orchestrate EMT. A delicate balance and fine-tuned cooperation of gene regulatory mechanisms is required for EMT to occur successfully, and until we resolve the unknowns in this network, we cannot hope to develop effective therapies against diseases that involve aberrant EMT such as cancer. In this review, we focus on data that challenge these unknown entities underlying EMT, starting with EMT stimuli followed by intracellular signaling through to epigenetic mechanisms and chromatin remodeling.

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Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

Cited by 26 publications

References 43 publications

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

SMARCA4/BRG1–Deficient Non–Small Cell Lung Carcinomas: A Case Series and Review of the Literature

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

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