Abemaciclib reduces glioblastoma stemness by targeting the GSK3b-mediated transcriptional regulation of CD44 and TCF7L2.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1226511 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32425690_1.fastq.gz | Fastqsanger.gz | |||
| SRR32425690_2.fastq.gz | Fastqsanger.gz | |||
| SRR32425691_1.fastq.gz | Fastqsanger.gz | |||
| SRR32425691_2.fastq.gz | Fastqsanger.gz | |||
| SRR32425692_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Glioblastoma multiforme (GBM) is the most common and deadliest glioma, originating from astrocytic progenitors or stem cells and affecting individuals of all ages. Current treatments include surgery, radiation therapy, chemotherapy, and combinations of these modalities. Temozolomide, the first-line chemotherapy for GBM, improves survival when combined with radiation but has limited success due to the tumor's inherent resistance to therapies. Cancer stem cells (CSCs), which exhibit self-renewal and differentiation capabilities, contribute to therapeutic resistance, making them a promising target for GBM therapy. Abemaciclib, a CDK4/6 inhibitor, effectively reduces tumor growth and sphere formation in GBM, although its exact mechanism remains unclear. Our data revealed that Abemaciclib significantly inhibited tumor sphere formation in U87MG and KNS42 cells by downregulating epithelial-mesenchymal transition (EMT)-associated genes, including CD44 and TCF7L2. Notably, silencing CD44 and TCF7L2 also led to a marked reduction in sphere formation. Phospho-kinase array analysis revealed that Abemaciclib reduces pGSK3β and pCREB in sphere cells. Western blotting confirmed that Abemaciclib diminishes pGSK3β-Y216 in parental cells, suggesting reduced kinase activity. Pharmacological inhibition of GSK3β also decreased CD44 and TCF7L2 expression. In an orthotopic animal model, Abemaciclib inhibited tumor formation, with reduced levels of pRB, pGSK3β, Ki67, and CD44 confirmed by immunohistochemistry. Analysis of TCGA and CGGA datasets showed that the mesenchymal GBM subtype (MES-GBM), associated with poor prognosis, has higher EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib decreased EMT-related genes. These findings suggest that Abemaciclib disrupts GSK3β-mediated EMT pathways, impairing CSC self-renewal and offering a potential therapeutic strategy for GBM.
2025-03-12 | GSE290174 | GEO
Project description:To understand the role of p53 in regulating stem cell population (CD24-CD44+) and stemness-associated miRNAs, we first compared miRNA expression profiles between human mammary epithelical cells knocked-down p53 and control cells. We then cross-referenced p53-regulated miRNAs with stemness-associated miRNAs analyzed from expression profiling of sorted CD24-CD44+ and non-CD24-CD44+ cell populations. Further biological experiments were performed with the miRNAs that are altered in CD24-CD44+ stem cell populations and also regulated by p53. Total RNAs, including miRNAs, extracted from CD24-CD44+ cells (labeled in Hy3) and non-CD24-CD44+ cells (labeled in Hy5) were hybridized on Exiqon miRCURY LNA arrays according to the manufacturer's protocol.
2011-02-01 | E-GEOD-25036 | biostudies-arrayexpress
Project description:To understand the role of p53 in regulating stem cell population (CD24-CD44+) and stemness-associated miRNAs, we first compared miRNA expression profiles between human mammary epithelical cells knocked-down p53 and control cells. We then cross-referenced p53-regulated miRNAs with stemness-associated miRNAs analyzed from expression profiling of sorted CD24-CD44+ and non-CD24-CD44+ cell populations. Further biological experiments were performed with the miRNAs that are altered in CD24-CD44+ stem cell populations and also regulated by p53.
2011-02-01 | GSE25036 | GEO
Project description:Identification of binding protein of TCF7L2-L by LC/MS
2025-01-13 | PXD048102 | Pride
Project description:This experiment follows the transcriptional response of human fibroblasts (BJ) to two different drug treatments (doxorubicin and abemaciclib) in comparison to treatment with vehicle (water). The two drugs are used in cancer care and their mechanism of action entails proliferative arrest. Doxorubicin is a member of the anthracycline family and acts as a topoisomerase II inhibitor. Abemaciclib is an inhibitor of the Cyclin Dependent Kinases (CDK) 4/6 which arrest cell cycle at the G1/S phase.
2021-11-29 | E-MTAB-7642 | biostudies-arrayexpress
Project description:Identification of TCF7L2 RNA binding proteins by LC/MS
2025-01-13 | PXD048312 | Pride
Project description:TCF7L2 is one of the strongest type 2 diabetes (T2DM) candidate genes to emerge from GWAS studies, but the mechanisms by which it regulates the pathways which are important in the pathogenesis of type 2 diabetes are unknown. Previous in vitro and in vivo studies have focused on the link between TCF7L2 and insulin secretion as an explanation for the association between TCF7L2 and T2DM. However, TCF7L2 and the Wnt/β-catenin pathway are important for metabolic zonation in the liver. This raises the interesting possibility that TCF7L2 may influence glucose homeostasis by regulating hepatic glucose production (HGP). To examine this question, we utilized the H4IIE cell as a model of HGP. Inhibition of HGP in H4IIE cells from lactate and pyruvate was highly sensitive to physiological concentrations of insulin and metformin. Silencing of TCF7L2 protein expression induced a 5-fold increase in basal HGP (P<0.0001), and this was accompanied by marked increase in the expression of several key gluconeogenic genes. FBPase, PEPCK and G6Pase mRNA were up-regulated 2.5-fold (P<0.0001), 1.4-fold (P<0.01) and 2.3-fold (P<0.0001), respectively, compared to scramble siRNA. Compared to their respective baseline values, insulin and metformin suppressed HGP equally in the scramble and TCF7L2 siRNA cells, but HGP remained elevated in TCF7L2 silenced cells due to the increased baseline HGP. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we investigated the direct transcriptional targets of TCF7L2 in hepatocytes. A total of 2119 ChIP peaks were detected, of which 36% were located inside gene boundaries and, overall, a total of 65% of all binding events were within 50 Kb of a gene. De novo motif analysis revealed remarkable conservation of the long and short TCF7L2 consensus binding sites in the rat hepatocytes. Pathway analysis showed that the top two disease categories over-represented in our dataset were “non-insulin dependent diabetes” (155 genes; P = 1.63 x 10-10) and “diabetes mellitus” (245 genes; P = 7.4 x 10-12). Inspection of genes in these categories revealed that TCF7L2 directly binds to multiple genes important in the regulation of glucose metabolism in the liver, including PEPCK, FBP1, IRS1, IRS2, AKT2 ADIPOR1, PDK4 and CPT1A. Our findings suggest a novel mechanism for the regulation of HGP by TCF7L2, and provide a possible explanation for the association of TCF7L2 polymorphisms with the incidence of T2DM. two samples: TCF7L2 ChIP-Seq and Input DNA
2011-09-12 | E-GEOD-28782 | biostudies-arrayexpress
Project description:TCF7L2 is one of the strongest type 2 diabetes (T2DM) candidate genes to emerge from GWAS studies, but the mechanisms by which it regulates the pathways which are important in the pathogenesis of type 2 diabetes are unknown. Previous in vitro and in vivo studies have focused on the link between TCF7L2 and insulin secretion as an explanation for the association between TCF7L2 and T2DM. However, TCF7L2 and the Wnt/β-catenin pathway are important for metabolic zonation in the liver. This raises the interesting possibility that TCF7L2 may influence glucose homeostasis by regulating hepatic glucose production (HGP). To examine this question, we utilized the H4IIE cell as a model of HGP. Inhibition of HGP in H4IIE cells from lactate and pyruvate was highly sensitive to physiological concentrations of insulin and metformin. Silencing of TCF7L2 protein expression induced a 5-fold increase in basal HGP (P<0.0001), and this was accompanied by marked increase in the expression of several key gluconeogenic genes. FBPase, PEPCK and G6Pase mRNA were up-regulated 2.5-fold (P<0.0001), 1.4-fold (P<0.01) and 2.3-fold (P<0.0001), respectively, compared to scramble siRNA. Compared to their respective baseline values, insulin and metformin suppressed HGP equally in the scramble and TCF7L2 siRNA cells, but HGP remained elevated in TCF7L2 silenced cells due to the increased baseline HGP. Using chromatin immunoprecipitation sequencing (ChIP-Seq), we investigated the direct transcriptional targets of TCF7L2 in hepatocytes. A total of 2119 ChIP peaks were detected, of which 36% were located inside gene boundaries and, overall, a total of 65% of all binding events were within 50 Kb of a gene. De novo motif analysis revealed remarkable conservation of the long and short TCF7L2 consensus binding sites in the rat hepatocytes. Pathway analysis showed that the top two disease categories over-represented in our dataset were “non-insulin dependent diabetes” (155 genes; P = 1.63 x 10-10) and “diabetes mellitus” (245 genes; P = 7.4 x 10-12). Inspection of genes in these categories revealed that TCF7L2 directly binds to multiple genes important in the regulation of glucose metabolism in the liver, including PEPCK, FBP1, IRS1, IRS2, AKT2 ADIPOR1, PDK4 and CPT1A. Our findings suggest a novel mechanism for the regulation of HGP by TCF7L2, and provide a possible explanation for the association of TCF7L2 polymorphisms with the incidence of T2DM.
2011-09-12 | GSE28782 | GEO
Project description:TCF7L2 regulates multiple metabolic pathways in hepatocytes through a transcriptional network involving HNF4M-NM-1 For the identification of Tcf7l2 target genes using a RNA-seq timecourse, and for identifying the binding sites of Tcf7l2 and Hnf4a, Tcf7l2 was silenced in rat H4IIE hepatocytes using siRNA for Tcf7l2 with a scrambled siRNA as control. Treatment times for RNA-seq samples were 3, 6, 9, 12, 15, 18, 48, and 96 hours, and for ChIP-seq samples 15 h. RNA-seq timecourse was performed in duplicate or triplicate, and the ChIP-seq in duplicate for Tcf7l2 and in singlicate for Hnf4a. The H4IIE-specific transcriptome was defined from an independent set of pooled 24 h siRNA treated samples (N=3 for siRNA for Tcf7l2 and N=3 for scrambled siRNA).
2014-11-24 | E-GEOD-53862 | biostudies-arrayexpress
Project description:We used chromatin immunoprecipitation combined with DNA sequencing to identify TCF7L2 localization on thalamic genome. We report that among putative TCF7L2 direct targets are thalamic terminal effector genes.
2020-07-24 | E-MTAB-9384 | biostudies-arrayexpress