Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression
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PROVIDER: PRJNA673195 | ENA |
REPOSITORIES: ENA
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Project description:Piwi proteins are a subfamily of Argonaute proteins that maintain germ cells in eukaryotes. However, the role of their human homologues in cancer stem cells and more broadly in cancer is poorly understood. Here, we report that the Piwi-like family members, including Piwil1 (Hiwi), are overexpressed in glioblastoma (GBM), with Piwil1 levels most frequently elevated. Piwil1 is enriched in glioma stem cells (GSCs) and helps to maintain their self-renewal. GSCs were transduces with control non-targeting shRNAs (shNT) and shPiwil1 (#1 and #2) and global gene expression was analyzed to identify Piwil1 downscream singalings.
2020-10-30 | GSE160437 | GEO
Project description:Piwi proteins are a subfamily of Argonaute proteins that maintain germ cells in eukaryotes. However, the role of their human homologs in cancer stem cells, and more broadly in cancer, is poorly understood. Here, we report that Piwi-like family members are overexpressed in glioblastoma (GBM), with Piwil1 (Hiwi) most frequently overexpressed (88%). Piwil1 is enriched in glioma stem-like cells (GSCs) to maintain self-renewal. Silencing Piwil1 in GSCs leads to global changes in gene expression resulting in cell-cycle arrest, senescence, or apoptosis. Piwil1 knockdown increases expression of the transcriptional co-regulator BTG2 and the E3-ubiquitin ligase FBXW7, leading to reduced c-Myc expression, as well as loss of expression of stem cell factors Olig2 and Nestin. Piwil1 regulates mRNA stability of BTG2, FBXW7, and CDKN1B. In animal models of GBM, Piwil1 knockdown suppresses tumor growth and promotes mouse survival. These findings support a role of Piwil1 in GSC maintenance and glioblastoma progression.
| S-EPMC7837390 | biostudies-literature
Project description:Modeling Malignant Progression in Glioma
| PRJNA762123 | ENA
Project description:Modeling Malignant Progression in Glioma
| PRJNA762124 | ENA
Project description:Modeling Malignant Progression in Glioma
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Project description:Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.
2024-07-29 | PXD054314 | Pride
Project description:Glioblastoma (GBM) is the most common and aggressive primary brain tumor with limited therapeutic options, possibly because of the highly tumorigenic subpopulations of stem cell-like cells. Mechanisms that sustain cancer stem cells are crucial to tumor progression. The polycomb group protein BMI1 (BMI1 proto-oncogene, polycomb ring finger) maintains cancer hallmarks including the glioblastoma stem-like cell (GSC) state. Ubiquitin-specific protease 22 (USP22) is highly expressed in and required for the maintenance of cancer stem cells (CSCs). Previously, we observed that forced expressed microRNA-218 in glioblastoma cells led to suppressed BMI1 expression. However, the pathways engaged by USP22 or driving BMI1 accumulation in GSCs remained elusive. Here, we found USP22 to be a novel deubiquitylase of BMI1. USP22 directly deubiquitylates and stabilizes BMI1. USP22 protein levels are elevated in tumor neurosphere. USP22 depletion induces BMI1 destabilization, and results in the inhibition of GSCs self-renewal by regulating a broad range of genes involved in glioma stemness and progression. Xenograft analyses using U87MG cells showed that both USP22 and BMI1 depletion attenuated tumor growth. Clinically, the expression levels of USP22 and BMI1 were positively correlated with those common targets like POSTN, HEY2, or PDGFRA and inversely correlated with ATF3 in human glioblastoma specimens. Taken together, our data reveals that USP22 functions as a novel deubiquitylase of BMI1 and inhibits self-renewal of GSCs by stabilizing BMI1. These findings also indicate that the USP22-BMI1 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioblastoma.
2017-01-01 | GSE89239 | GEO
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:We compared a large panel of human glioblastoma stem-like (GS) cell lines, corresponding primary tumors and conventional glioma cell lines to identify cell lines that preserve the transcriptome of human glioblastomas most closely, thereby allowing identification of shared therapeutic targets. We used Affymetrix HG-U133 Plus 2.0 microarrays to compare human glioblastoma stem-like (GS) cell lines, corresponding primary tumors and conventional glioma cell lines. We extracted total RNA from 32 conventional glioma cell lines, 12 GS cell lines (8 in two different passages), 7 clonal sublines derived from two GS lines, 12 original tumors, and 4 monolayer cultures established from the same tumors as GS-lines using standard serum conditions.
2011-02-12 | E-GEOD-23806 | biostudies-arrayexpress
Project description:We compared a large panel of human glioblastoma stem-like (GS) cell lines, corresponding primary tumors and conventional glioma cell lines to identify cell lines that preserve the transcriptome of human glioblastomas most closely, thereby allowing identification of shared therapeutic targets. We used Affymetrix HG-U133 Plus 2.0 microarrays to compare human glioblastoma stem-like (GS) cell lines, corresponding primary tumors and conventional glioma cell lines.
2011-02-12 | GSE23806 | GEO