Silencing of PFKFB4 in Glioblastoma Stem-like Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108742 | GEO | 2019/01/05
REPOSITORIES: GEO
Similar Datasets
Project description:Glioblastoma is one of the most aggressive primary brain tumours in adults, with a dismal median overall survival of only 14 months after diagnosis1,2. Glioblastoma stem-like cells (GSCs), are particularly resistant to current therapies3,4, capable of self-renewal and tumour initiation5,6 and are hence thought to be major contributors to patient relapse. Glycolysis gene 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is an essential gene for GSC survival, and is upregulated in these cells compared with in normal brain7. However, the mode of action of PFKFB4 in GSCs is unknown. Here we show a new role for PFKFB4 in the regulation of Hypoxia Inducible Factor 1 alpha (HIF1α) in GSCs. In a metabolic tracing study, we found that silencing PFKFB4 in GSCs resulted in a global downregulation of glucose metabolism. Gene expression profiling of PFKFB4-silenced GSCs revealed a downregulation of HIF1α target genes, and HIF1α protein levels are dramatically reduced in PFKFB4-silenced GSCs and other cancer cell lines. Finally, through mass spectrometric analysis of immunoprecipitated PFKFB4, we identified the ubiquitin E3 ligase, F box only protein 28 (FBXO28), as a new interaction partner of PFKFB4, which we show to regulate ubiquitylation and subsequent proteasomal degradation of HIF1α. Crucially, this newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF1α in a cancer specific manner. Compounds which disrupt the interaction between PFKFB4 and FBXO28 could be interesting therapeutic agents against glioblastoma and other cancer entities in which PFKFB4 regulates HIF1α stability.
2022-10-13 | PXD009807 | Pride
Project description:In order to investigate the crucial role of PRKCI in glioblastoma stem-like cell (GSC) survival, gene expression microarray-based transcriptome analysis was conducted on GSCs transduced for 4 days with PRKCI shRNA compared with GSCs transduced with shNT.
2016-01-21 | GSE77030 | GEO
Project description:Silencing of PFKFB4 in Glioblastoma Stem-like Cells
| PRJNA428471 | ENA
Project description:Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.
2024-11-05 | GSE262995 | GEO
Project description:Glioblastoma progression and recurrence are suggested to be derived by glioblastoma stem-like cells (GSCs). There is limited knowledge about the expression and therapy response of LGR5 in GSCs. We have investigated the role of LGR5 in glioblastoma by knocking down LGR5 using short hairpin RNA targeting LGR5 mRNA (shLGR5) and non-target RNA (shNT) as control.
2018-10-18 | GSE109867 | GEO
Project description:Patient-derived primary GSCs were established from discarded specimens obtained from glioblastoma (GBM) patients undergoing surgery at UT Health San Antonio. We examined global transcriptional changes by RNA-sequencing using patient derived glioma stem cells (GSCs) transduced with either control shRNA or Reticulocalbin-3 (RCN3) shRNA. RNA-seq studies showed downregulation of genes related to translation, ribosome, and cytokine signaling and upregulation of genes related to immune response, stem cell differentiation, and extracellular matrix.
2023-04-19 | GSE226990 | GEO
Project description:Glioblastoma stem cells (GSCs) fate is controlled by environmental cues, among which cytokines play a crucial role. The transforming growth factor β (TGFβ) family signaling pathways controls GSCs. On one hand, TGFβ promotes cell proliferation in GBM, it induces the expression of platelet-derived growth factor-B (PDGFB). Moreover, TGFβ, via its signaling mediators Smad2/3, induces the expression of the cytokine leukemia inhibitory factor (LIF) and Sox4, which in turn enhances the expression of the stem cell transcription factor Sox2; this increases the self-renewal capacity of the GSCs and their stemness characteristics, and enhances the GSC tumor-initiating potential. On the other hand, Bone morphogenic proteins (BMPs) are known to promote GSC differentiation towards the astrocytic phenotype. To further understand which genes are regulated by TGFβ and BMP7 in GSCs we performed a microarray in the Affymetrix HTA2 platform in three different glioblastoma cell line, U2987, and two patient-derived glioblastoma stem cells, U3031MG and U3034MG, in the presence or absence of 5 ng/ml of TGFβ or 30 ng/ml BMP7 for 24 h, three biological replicates per condition.
2020-09-01 | E-MTAB-9076 | biostudies-arrayexpress
Project description:The persistence of Glioblastoma Stem-like Cells (GSCs) may account for the high lethality of glioblastoma patients. The GSC reservoir typically resides close to blood vessels, where these cells receive maintenance signals. Upon unfavorable conditions, GSCs escape these niches and spread by exploiting the pre-existing brain vasculature. In both scenarios, GSCs interact with the vascular interface, including the endothelial cells and their matrix. How cell adhesion encountered in their microenvironment serves GSC fate remains ill-defined. By combining ex vivo models, including decellularized matrices, cell co-culture, and organotypic slices, we identified that Junctional Adhesion Molecule C (JAMC) tethers GSCs to endothelial surface. Functionally, JAMC-/- GSCs exhibit an extended spreading on various endothelial-borne supports, with exacerbated invasive, migratory, and mesenchymal-like behaviors, that eventually eroded the survival of GSC tumor-bearing mice. Label-free quantitative proteomics next unveiled that JAMC deletion elicits an up-regulation of integrin expression, concurrent to a down-regulation of the integrin negative regulator, SHARPIN. Data mining of spatial transcriptomics confirmed the association between glioblastoma invasion and the expression pattern of JAMC. While JAMC may provide a retention signal in endothelial niches, the landscape of adhesion molecules anchoring GSCs to vascular surfaces may ultimately coordinate cell migration in defined glioblastoma territories.
2025-08-28 | PXD062679 | Pride
Project description:Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.
2021-09-25 | GSE135306 | GEO
Project description:Glioblastoma is a major unmet clinical need characterized by striking inter- and intra-tumoral heterogeneity and a population of glioblastoma stem cells (GSCs), conferring aggressiveness and therapy resistance. GSCs communicate through a network of tumor-tumor connections (TTCs), including nanotubes and microtubes, promoting tumor progression. However, very little is known about the mechanisms underlying TTC formation and overall GSC morphology. As GSCs closely resemble neural progenitor cells during neurodevelopment, we hypothesised that GSCs’ morphological features affect tumour progression. We identified GSC morphology as a new layer of tumoral heterogeneity with important consequences on GSC proliferation. Strikingly, we showed that the neurodevelopmental morphoregulator ADD3, is sufficient and necessary for maintaining proper GSC morphology, TTC abundance and cell cycle progression as well as required for cell survival. Remarkably, both the effects on cell morphology and proliferation depend on the stability of actin cytoskeleton. Hence, cell morphology and its regulators play a key role in tumor progression by mediating cell-cell communication. We thus propose that GSC morphological heterogeneity holds the potential to identify new therapeutic targets and diagnostic markers.
2024-11-12 | GSE280761 | GEO