Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway
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PROVIDER: PRJNA820005 | ENA |
REPOSITORIES: ENA
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Project description:Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway (ChIP-seq)
| PRJNA820827 | ENA
Project description:Brg1 is a subunit of SWI/SNF chromatin remodeling complex. To clarify the role of Brg1 for the progression and metastasis of pancreatic ductal adenocarcinoma (PDAC), we generated a PDAC mouse model with a dual recombinase system (Brg1 lox/lox; Pdx1-Flp; Kras FSF-G12D; Trp53 frt/frt; Rosa26 FSF-CreERT2) which enabled to ablate Brg1 in established PDAC with tamoxifen treatment. We established cancer cell lines derived from PDAC tumors developed in those mice and investigated the effect of Brg1 ablation on PDAC cell proliferation and metastasis. In order to determine the genes expression in Brg1-deleted mouse PDAC cells, we conducted a transcriptomic analysis using microarray using Brg1 wild type and Brg1-deleted mouse PDAC cells.
2022-04-30 | GSE199442 | GEO
Project description:Brg1 is a subunit of SWI/SNF chromatin remodeling complex. To clarify the role of Brg1 for the progression and metastasis of pancreatic ductal adenocarcinoma (PDAC), we generated a PDAC mouse model with a dual recombinase system (Brg1 lox/lox; Pdx1-Flp; Kras FSF-G12D; Trp53 frt/frt; Rosa26 FSF-CreERT2) which enabled to ablate Brg1 in established PDAC with tamoxifen treatment. We established cancer cell lines derived from PDAC tumors developed in those mice and investigated the effect of Brg1 ablation on PDAC cell proliferation and metastasis. In order to determine the genes that Brg1 directly regulates, we conducted a chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) analysis for Brg1 and histone modifications (H3K27ac and H3K27me3) using Brg1 wild type and Brg1-deleted mouse PDAC cells.
2022-04-30 | GSE199610 | GEO
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:DEAD-box RNA-binding proteins (RBPs) play a significant role in RNA metabolism to achieve cellular homeostasis, including miRNA biogenesis and transcription. Hypoxia induces stemness cell-like characteristics in cancer cells and promotes malignant progression. Despite the fact that hypoxia can induce the changes in protein and RNA modification, thereby regulating downstream gene expressions, how modifications at different molecular layers interplay with each other are poorly understood. Here we show that hypoxia induces HectH9-mediated K63-linked polyubiquitination of the DEAD-box protein DDX17 as well as reduces N6-methyladenosine (m6A) marks in pri-miRNAs. While m6A potentiates DDX17 binding to pri-miRNAs, decreased m6A modifications of pri-miRNAs and increased polyubiquitination of DDX17 under hypoxia lead to decreased DDX17 binding to pri-miRNAs binding. These events enhance the association of DDX17 with the ubiquitin receptor p300 and lead to a decrease in miRNA biogenesis, especially for miRNAs regulating stemness and stemness-related genes. In addition, polyubiquitinated DDX17 together with p300 upregulates H3K56Ac levels on the stemness and stemness-related genes, resulting in enhancement of tumor initiating ability. Post-transcriptionally, decreased miRNA production, including those targeting stemness genes or stemness-related genes, also facilitates tumor initiation. Together, hypoxia triggers DDX17 poly-ubiquitination, which orchestrates dual mechanisms to increase tumor initiating ability and promote tumor progression.
2018-03-09 | PXD006059 | JPOST Repository
Project description:Metastasis is responsible for the majority of breast cancer (BrCa) deaths; however, the underlying mechanisms remain largely elusive. Here, we report that suppression of MBD2 alternative splicing under hypoxia, which favors the production of MBD2a, facilitates BrCa metastasis. Specifically, we found that MBD2a promotes, whereas its less-known short form MBD2c suppresses metastasis. We elucidate that HIF-1 activation under hypoxia facilitates MBD2a production via repression of SRSF2-mediated alternative splicing and, as a result, the elevated MBD2a outcompetes MBD2c for binding to the promoter CpG islands to activate the expression of FZD1, thereby promoting EMT and metastasis. Strikingly, clinical data reveals significantly correlated expression pattern of MBD2a and MBD2c with the invasiveness of malignancy, indicating the opposing roles for MBD2 splicing variants in regulating human BrCa metastasis. Thus, our findings establish a novel link between MBD2 switching and tumor metastasis, and provide promising therapeutic strategy and predictive biomarkers for hypoxia-driven BrCa metastasis.
2021-02-01 | GSE151952 | GEO
Project description:Ovarian cancer (OC) is the most lethal gynecological cancer due to its late diagnosis and, importantly, its high rate of chemoresistance. Hypoxia in solid tumors is an important source of chemoresistance that can determine poor patient prognosis. Such chemoresistance relies on the presence of cancer stem cells (CSCs), and hypoxia promotes their generation through transcriptional activation by HIF transcription factors. We use OC cell lines, xenograft models, OC patient samples, transcriptional databases, iPSCs and ATAC-seq. We show here that hypoxia induces the formation of ovarian CSCs through transcriptional activation of the PLD2 gene encoding phospholipase D2. HIF-1 activates PLD2 transcription through hypoxia response elements located within PLD2 promoter and an intronic enhancer. PLD2 overexpression leads to similar effects than hypoxia, increasing CSC-like features, stemness gene expression and enhancing cell reprogramming in OC cells, as well as chromatin accessibility around stemness genes detected by ATAC-seq. Conversely, PLD2 depletion in hypoxia partially suppresses these effects, indicating that PLD2 is a major determinant of hypoxia-induced CSC generation in OC. Indeed, PLD2 expression is high in OC patients leading to poor survival and a transcriptional switch in the genes related to the response to hypoxia and stemness. Finally, we demonstrate that PLD2 overexpression provokes resistance to platinum-based chemotherapy and that combination of cisplatin with pharmacological inhibition of PLD2 suppresses such resistance. Altogether, our work highlights the importance of the HIF-1-PLD2 axis for CSC generation and chemoresistance in OC and proposes an alternative treatment for patients with high PLD2 expression.
2023-08-06 | GSE210599 | GEO
Project description:The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the ATPase subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression, however aberrant remodeling and gene expression can result in cancer. The function and localization on chromatin of the SWI/SNF complex depends on the protein makeup of the complex. Here we report the protein-protein interactions of wild-type BRG1 or mutant BRG1 in which the HSA domain has been deleted (BRG1-HSA). We demonstrate the interaction of BRG1 with most SWI/SNF complex members and a failure of a number of these members to interact with BRG1-HSA. These results demonstrate that the HSA domain of BRG1 is a critical interaction platform for the correct formation of SWI/SNF remodeling complexes.
2023-02-15 | PXD029647 | Pride
Project description:Chromatin remodeling factor BRG1 regulates stemness and chemosensitivity of glioma initiating cells
| PRJNA478991 | ENA
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. In the present study we used different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumours we found that Fat1 deletion accelerated tumour initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumour stemness and spontaneous metastasis. Transcriptional and chromatin profiling revealed that Yap1 and Sox2 are involved in promoting and stabilizing hybrid EMT state. To unravel the molecular mechanisms by which FAT1 (a protein located on the plasma membrane), lead to the transcriptional changes, we performed phosphor-proteomic analysis of A388 FAT1 WT human SCC cell lines and A388 FAR1 CRISPR KO. This analysis revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumours with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2021-01-18 | PXD022268 | Pride