ABSTRACT
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ABSTRACT
The perivascular niche in glioma is critical for the maintenance of glioma stem cells (GSCs), and tumour-endothelial cell (EC) communication impacts tumourigenesis in ways that are incompletely understood. Here, we show that glioma-associated human endothelial cells (GhECs), a main component of the perivascular niche, release extracellular vesicles (EVs) that increase GSC proliferation and tumour-sphere formation. GSCs treated with GhEC-EVs create a significantly greater tumour burden than do untreated GSCs in orthotopic xenografts. Mechanistic, analysis of EVs content identified CD9 as a mediator of the effects on GSCs. CD9 can activate the BMX/STAT3 signalling pathway in GSCs. Our results illuminate the tumour-supporting role of ECs by identifying that EC-derived EVs transfer of CD9 during intercellular communication, thereby enhancing the aggressiveness of glioblastoma by specifically maintaining GSCs.
ABSTRACT
Histone methylation is essential for regulating gene expression during organogenesis to maintain stem cells and execute a proper differentiation program for their descendants. Here we show that the COMPASS family histone methyltransferase co-factor ASH2L is required for maintaining neural progenitor cells (NPCs) and the production and positioning of projection neurons during neocortex development. Specifically, loss of Ash2l in NPCs results in malformation of the neocortex; the mutant neocortex has fewer neurons, which are also abnormal in composition and laminar position. Moreover, ASH2L loss impairs trimethylation of H3K4 and the transcriptional machinery specific for Wnt-ß-catenin signaling, inhibiting the proliferation ability of NPCs at late stages of neurogenesis by disrupting S phase entry to inhibit cell cycle progression. Overexpressing ß-catenin after ASH2L elimination rescues the proliferation deficiency. Therefore, our findings demonstrate that ASH2L is crucial for modulating Wnt signaling to maintain NPCs and generate a full complement of neurons during mammalian neocortex development.
Subject(s)
DNA-Binding Proteins/metabolism , Neocortex/cytology , Neocortex/metabolism , Neural Stem Cells/metabolism , Neurogenesis/genetics , Neurons/metabolism , Transcription Factors/metabolism , Wnt Signaling Pathway/genetics , Animals , Cell Proliferation/genetics , Chromatin Immunoprecipitation Sequencing , DNA-Binding Proteins/genetics , Gene Expression Regulation, Developmental/genetics , Gene Ontology , Histones/chemistry , Histones/metabolism , Methylation , Mice , Neocortex/embryology , Neurogenesis/physiology , Neurons/cytology , RNA-Seq , S Phase Cell Cycle Checkpoints/genetics , Telencephalon/cytology , Telencephalon/embryology , Telencephalon/metabolism , Transcription Factors/genetics , Transcriptional Activation , Up-Regulation , beta Catenin/metabolismABSTRACT
Glioma, the most common primary malignancy in the brain, has high recurrence and lethality rates, and thus, elucidation of the molecular mechanisms of this incurable disease is urgently needed. Poly-pyrimidine tract binding protein (PTBP1, also known as hnRNP I), an RNA-binding protein, has various mechanisms to promote gliomagenesis. However, the mechanisms regulating PTBP1 expression are unclear. Herein, we report a novel natural antisense noncoding RNA, PTB-AS, whose expression correlated positively with PTBP1 mRNA. We found that PTB-AS significantly promoted the proliferation and migration in vivo and in vitro of glioma cells. PTB-AS substantially increased the PTBP1 level by directly binding to its 3' UTR and stabilizing the mRNA. Furthermore, staphylococcal nuclease domain-containing 1 (SND1) dramatically increased the binding capacity between PTB-AS and PTBP1 mRNA. Mechanistically, PTB-AS could mask the binding site of miR-9 in the PTBP1-3' UTR; miR-9 negatively regulates PTBP1. To summarize, we revealed that PTB-AS, which maintains the PTBP1 level through extended base pairing to the PTBP1 3' UTR with the assistance of SND1, could significantly promote gliomagenesis.
Subject(s)
Endonucleases/metabolism , Glioma/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Polypyrimidine Tract-Binding Protein/genetics , RNA Stability , RNA, Antisense/genetics , RNA, Messenger/genetics , 3' Untranslated Regions , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , RNA Interference , RNA, Long Noncoding/genetics , RNA-Binding Proteins/metabolismABSTRACT
Acidosis is a significant feature of the tumor microenvironment in glioma, and it is closely related to multiple biological functions of cancer stem cells. Here, we found that the self-renewal ability, the mitochondrial activity and ATP production were elevated in stem cell-like glioma cells (SLCs) under acidic microenvironment, which promoted and maintained the stemness of SLCs. Under acidosis, 25-hydroxy vitamin D3-24-hydroxylase (CYP24A1) was upregulated and catalyzed the fast degradation of 1α,25(OH)2D3. We further revealed that the active form of vitamin D (1α,25(OH)2D3) could inhibit the expression of stemness markers, attenuate acidosis-induced increase of self-renewal ability and mitochondrial respiration in stem cell-like glioma cells. Our study indicates that the acidosis-CYP24A1-vitamin D pathway may be a key regulator of the cancer stem cell phenotype in malignant glioma and point out the potential value for the utilization of vitamin D to target cancer stem cells and to restrain the growth of malignant glioma in the future.
