Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells

Bayın, N. Sumru; Frenster, Joshua D.; Sen, Rajeev; Si, Sheng; Modrek, Aram S.; Galifianakis, Nataliya; Dolgalev, Igor; Ortenzi, Valerio; Illa-Bochaca, Irineu; Khahera, Anadjeet; Serrano, Jonathan; Chiriboga, Luis; Zagzag, David; Golfinos, John G.; Doyle, Werner; Tsirigos, Aristotelis; Heguy, Adriana; Chesler, Mitchell; Barcellos‐Hoff, Mary Helen; Snuderl, Matija; Placantonakis, Dimitris G.

doi:10.18632/oncotarget.18117

Cited by 58 publications

(42 citation statements)

References 73 publications

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“…Human Brian Tumor Models. Patient-derived glioma lines, including DIPG lines (see Table S1 for source), were cultured in tumor stem cell media as described (37,38). Human neural stem cells were derived and cultured as described previously (39).…”

Section: Cell Culture Models and Tissue Preparationmentioning

confidence: 99%

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Stafford

Lee

Voigt³

et al. 2018

Preprint

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A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity. MAIN TEXT

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Section: Cell Culture Models and Tissue Preparationmentioning

confidence: 99%

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Stafford

Lee

Voigt³

et al. 2018

Preprint

Self Cite

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“…We did not see a significant difference in the onset of trapping voltages between U251 and SF‐U251. The similarity could be due to heterogenous nature of GSC subpopulation . SF‐U251 is a heterogenous subpopulation with some cells close to U251 phenotype.…”

Section: Discussionmentioning

confidence: 96%

The feasibility of using dielectrophoresis for isolation of glioblastoma subpopulations with increased stemness

et al. 2019

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Cancer stem cells (CSCs) are aggressive subpopulations with increased stem‐like properties. CSCs are usually resistant to most standard therapies and are responsible for tumor repropagation. Similar to normal stem cells, isolation of CSCs is challenging due to the lack of reliable markers. Antigen‐based sorting of CSCs usually requires staining with multiple markers, making the experiments complicated, expensive, and sometimes unreliable. Here, we study the feasibility of using dielectrophoresis (DEP) for isolation of glioblastoma cells with increased stemness. We culture a glioblastoma cell line in the form of neurospheres as an in vitro model for glioblastoma stem cells. We demonstrate that spheroid forming cells have higher expression of stem cell marker, nestin. Next, we show that dielectric properties of neurospheres change as a result of changing culture conditions. Our results indicate that spheroid forming cells need higher voltages to experience the same DEP force magnitude compared to normal monolayer cultures of glioblastoma cell line. This study confirms the possibility of using DEP to isolate glioblastoma stem cells.

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“…Notch signaling pathway plays essential roles in proliferation, migration and even maintaining cellular quiescence (48). The cleavage of notch receptor by γ-secretase after binding of ligands like jagged or delta family leads to the translocation of Notch intracellular domain (NICD) to the nucleus, thereby activating notch-related downstream targets (49). Afterwards, notch signaling is terminated by triggering ubiquitinated degradation of NICD PEST domain with the absence of SCF E3 ubiquitin ligase (50,51).…”

Section: Discussionmentioning

confidence: 99%

Loss of PLK2 Induces Acquired Resistance to Temozolomide in GBM via Activation of Notch Signaling

Alafate

et al. 2020

Preprint

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BackgroundGlioblastoma (GBM) isa lethal type of primary brain tumor with a median survival less than 15 months.Despiting the recent improvements of comprehensive strategies,the outcomes for GBM patients remain dismal.Accumulating evidence indicates that rapid acquired chemoresistance is the major cause ofGBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. MethodsTranscriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. ResultsIn this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, immigration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1.ConclusionLoss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

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Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells

Cited by 58 publications

References 73 publications

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

The feasibility of using dielectrophoresis for isolation of glioblastoma subpopulations with increased stemness

Loss of PLK2 Induces Acquired Resistance to Temozolomide in GBM via Activation of Notch Signaling

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