Irradiation of healthy brain alters expression of genes involved in cell motility and invasiveness of glioblastoma
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PROVIDER: PRJNA556205 | ENA |
REPOSITORIES: ENA
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2020-10-14 | GSE134711 | GEO
Project description:There is some emerging evidence that members of the Schlafen (SLFN) family of proteins mediate antineoplastic responses, but the mechanisms accounting for these effects are not known. We provide evidence that human SLFN5, an interferon (IFN)- inducible member of the family, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of matrix metalloproteinases (MMP)-1 and -13 and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression.
2015-06-01 | GSE64399 | GEO
Project description:UV irradiation alters TFAM binding specificity and compaction of DNA
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Project description:Glioblastoma (GBM), the most prevalent primary brain tumor, remains incurable due to the presence of cancer stem cells (CSC), which can be isolated as tumorspheres (TS) that exhibits classical characteristics of CSCs including stemness and invasiveness. The significantly elevated expression of Bruton’s tyrosine kinase (BTK) in GBM tissues identifies BTK as a potential therapeutic target in GBM. Consequently, ibrutinib, an FDA-approved BTK inhibitor for hematological malignancies, has been repurposed as a candidate for GBM treatment, demonstrating inhibitory effects on proliferation, stemness, and invasiveness of GBM cell lines and TSs. However, its broad-spectrum activity targeting other Tec family kinases and members of the epidermal growth factor receptor (EGFR) family, poses potential life-threatening risks, necessitating the development of more selective alternatives. To address this, BTK selective analogs (SPA1758, SPA1763, SPA8004, SPA8007, SPA8009) were synthesized with the aim of targeting two key characteristics of GBM TSs: stemness and invasiveness. WST and ATP assays identified SPA8007 and SPA8009 as the most effective candidates with superior cytotoxic effects in TSs. Additionally, both SPA8007 and SPA8009 significantly inhibited neurosphere formation and reduced invasiveness in GBM TSs. Furthermore, SPA8007 demonstrated improved survival rates in a GBM xenograft mouse model and reduced the expression of invasiveness markers significantly, as observed in immunohistochemistry (IHC) analysis. These findings highlight SPA8007 as potential novel chemotherapeutic agents with high specificity and efficacy to enhance GBM therapy.
2025-04-01 | GSE288022 | GEO
Project description:Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence.
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Project description:Tumor invasion into surrounding stromal tissue is a hallmark of high-grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor, 5-AzaC, potently blocks the increased cell motility and invasiveness induced by Src activation. A proteomic screen for chromatin regulators acting downstream of activated Src identified the replication-dependent histone chaperone CAF1 as an important factor for Src-mediated increased cell motility and invasion. We show Src causes a 5-AzaC-sensitive decrease in both mRNA and protein levels of the p150 (CHAF1A) and p60 (CHAF1B), subunits of CAF1. Depletion of CAF1 in untransformed epithelial cells using siRNA was sufficient to recapitulate the increased motility and invasive phenotypes characteristic of transformed cells without activation of Src. Maintaining high levels of CAF1 by exogenous expression suppressed the increased cell motility and invasiveness phenotypes when Src was activated. These data identify a critical role of CAF1 in the dysregulation of cell invasion and motility phenotypes seen in transformed cells and also highlight an important role for epigenetic remodeling through DNA methylation for Src-mediated induction of cancer phenotypes.
2016-12-20 | PXD005494 | Pride
Project description:Mitochondria lack nucleotide excision repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids and binds differentially to certain forms of DNA damage. As such, TFAM has emerged as a candidate for protecting mtDNA or sensing damage. To examine the possibilities that TFAM might protect DNA from damage or act as a damage sensing protein for irreparable forms of mtDNA damage, we used live-cell imaging and HeLa cell-based assays, atomic force microscopy (AFM), and high-throughput protein-DNA binding assays to characterize the binding properties of human TFAM to ultraviolet-C (UVC) irradiated DNA and the cellular consequences of UVC irradiation. Our cell data show increased TFAM mRNA after exposure and suggest an increase in mtDNA degradation without a loss in mitochondrial membrane potential that might trigger mitophagy. Our protein-DNA binding assays indicate a reduction in sequence specificity of TFAM following UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA in vitro, we do not observe any protective effect of increased TFAM protein on DNA damage formation in cells or in vitro. Increased TFAM protein did not alter levels of mtDNA damage over time after UVC exposure in vivo, but knockdown of TFAM did alter mtDNA damage levels in HeLa cells both at baseline and after UVC exposure. Taken together, these studies indicate that UVC-induced DNA damage alters TFAM binding and promotes compaction by TFAM in vitro. We hypothesize that that TFAM may act as a damage sensing protein in vivo, sequestering damaged genomes to prevent mutagenesis by facilitating removal or suppression of replication.
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Project description:Chromatin remodeler proteins exert an important function in promoting dynamic modifications in the chromatin architecture, performing a central role in regulating gene transcription. Deregulation of these molecular machines may lead to striking perturbations in normal cell function. The CHD7 gene is a member of the chromodomain helicase DNA-binding family and, when mutated, has been shown to be the cause of the CHARGE syndrome, a severe developmental human disorder. Moreover, CHD7 has been described to be essential for neural stem cells and it is also highly expressed or mutated in a number of human cancers. However, its potential role in glioblastoma has not yet been tested. Here, we show that CHD7 is up-regulated in human glioma tissues and we demonstrate that CHD7 knockout (KO) in LN-229 glioblastoma cells suppresses anchorage-independent growth and spheroid invasion in vitro. Additionally, CHD7 KO impairs tumor growth and increases overall survival in an orthotopic mouse xenograft model. Conversely, ectopic overexpression of CHD7 in LN-428 and A172 glioblastoma cell lines increases cell motility and invasiveness in vitro and promotes LN-428 tumor growth in vivo. Finally, RNA-seq analysis revealed that CHD7 modulates a specific transcriptional signature of invasion-related target genes. Further studies should explore clinical-translational implications for glioblastoma treatment.
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Project description:To investigate effects on mRNA expression through treatment with FG-3019, irradiation and their combination to gain mechanistic hypotheses on the effects of these treatments on glioblastoma stem cell like cells which have been observed in vitro and in vivo. mRNA expression was measured 6 h after treatment with FG-3019, irradiation and their combination. 3 biological replicates were analyzed for each treatment condition (control, FG-3019, irratiation and FG-3019+irradiation)
2014-08-30 | E-GEOD-60921 | biostudies-arrayexpress
Project description:Histone deacetylase inhibitors impair glioblastoma cell motility and proliferation
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