Glioblastoma Invasion Research Articles

The self-organized structure of glioma oncostreams and the disruptive role of passive cells

Oncostreams are self-organized structures formed by spindle-like, elongated, self-propelled cells recently described in glioblastomas and especially in gliosarcomas. Cells within these structures either move as large clusters in one main direction, flocks, or as linear, intermingling collections of cells advancing in opposite directions, streams. Round, passive cells are also observed, either inside or segregated from the oncostreams. Here we generalize a recently formulated particle-field approach to investigate the genesis and evolution of these structures, first showing that, in systems consisting only of identical self-propelled cells, both flocks and streams emerge as self-organized dynamic configurations. Flocks are the more stable configurations, while streams are transient and usually originate in collisions between flocks. Stream degradation is easier at low self-propulsion speeds. In systems consisting of both motile and passive cells, the latter block stream formation and accelerate their degradation and flock stabilization. Since the flock appears to be the most effective invasive structure, we thus argue that a phenotype mixture (motile and passive cells) may favor glioblastoma invasion. hlBy relating cellular properties to the observed outcome, our model shows that oncostreams are self-organized structures that result from the interplay between speed, shape, and steric repulsion.

Transcription factor YY1-activated GNG5 facilitates glioblastoma cell growth, invasion, stemness and glycolysis through Wnt/β-catenin pathway

G protein subunit Gamma 5 (GNG5) has been found to be involved in regulating glioma progression. However, its function and mechanism in glioblastoma (GBM) progression need to be further elucidated. GBM cell proliferation, apoptosis, invasion and stemness were assessed by cell counting kit 8 assay, EdU assay, flow cytometry, transwell assay and sphere formation assay. The mRNA and protein levels of GNG5 and Yin Yang 1 (YY1) were determined by quantitative real-time PCR and western blot (WB). Detection of the glucose consumption, lactate production and ATP/ADP ratios were used to assess cell glycolysis. Besides, Wnt/β-catenin pathway-related protein levels were examined by WB. Mice xenograft model was also constructed to explore GNG5 roles in vivo. GNG5 was highly expressed in GBM, and its silencing inhibited GBM cell proliferation, invasion, stemness and glycolysis, while promoted apoptosis. Transcription factor YY1 could bind to the GNG5 promoter region and induce its expression. GNG5 overexpression reversed the inhibitory effects of YY1 silencing on GBM cell growth, invasion, stemness and glycolysis. YY1/GNG5 axis could activate the Wnt/β-catenin pathway, and Wnt/β-catenin pathway agonists SKL2001 could revert the effects of GNG5 silencing on GBM cell progression. Furthermore, GNG5 facilitated GBM tumor growth by mediating the Wnt/β-catenin pathway. YY1-mediated GNG5 promoted GBM progression through the Wnt/β-catenin pathway.

SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins.

The poor surgical efficacy and recurrence of glioblastoma (GBM) are due to its lack of visible infiltrative features. Our bioinformatics study suggests that low expression of small ubiquitin-like modifier (SUMO)-specific protease 7 (SENP7) indicates poor prognosis in GBM. This study investigated the effect of SENP7 expression on the invasion, migration, and proliferation of GBM cells and aims to identify the SUMO target proteins affected by SENP7. SENP7 expression was analyzed in eight GBM tumor samples and four GBM cell lines, comparing them to normal brain tissue. The effect of SENP7 overexpression on GBM LN229 cell migration, invasion, and proliferation was examined through in vitro assays. Furthermore, four SUMO target proteins involved in tumor invasion and proliferation (CDK6, matrix metalloproteinase-9 [MMP9], AKT, and HIF-1α) were studied to explore SENP7's molecular mechanism. SENP7 expression was significantly lower in GBM tumors compared to normal tissue. SENP7 overexpression in LN229 cells inhibited migration and invasion without affecting proliferation. Overexpression reduced the levels of MMP9, AKT, and HIF-1α, but not CDK6. Immunohistochemical analysis showed decreased MMP9 and CD31 levels, suggesting reduced tumor invasion and angiogenesis. However, SENP7 overexpression did not affect tumor growth in vivo. SENP7 inhibits GBM invasion by dissociating proteins associated with tumor invasion from SUMO2/3, providing a potential target for future GBM therapies.

Exploring the Mechanism of Sempervirine Inhibiting Glioblastoma Invasion Based on Network Pharmacology and Bioinformatics

Background: Invasion is an important characteristic of the malignancy of glioblastoma (GBM) and a significant prognostic factor. Sempervirine (SPV), a yohimbine-type alkaloid, has been proven to inhibit GBM cells proliferation in previous research and found to have a potential effect in anti-invasion, but its mechanism of anti-invasion is still unknown. Methods: To explore its pharmacodynamics in inhibiting GBM cell invasion in this study, we combined network pharmacology and bioinformatics to comprehensive exploratory analysis of SPV and verified the mechanism in vitro. Results: Firstly, targets of SPV and invasion-related genes were collected from public databases. Moreover, GBM samples were obtained to analyze differentially expressed genes (DEGs) from The Cancer Genome Atlas (TCGA). Then, the relevant targets of SPV inhibiting GBM invasion (SIGI) were obtained through the intersection of the three gene sets. Further, GO and KEGG analysis showed that the targets of SIGI were heavily enriched in the AKT signaling pathway. Subsequently, based on the method of machine learning, a clinical prognostic model of the relevant targets of SIGI was constructed using GBM samples from TCGA and the Gene Expression Omnibus (GEO). A four-genes model (DUSP6, BMP2, MMP2, and BMP2) was successfully constructed, and Vina Scores of MMP2 and MMP13 in molecular docking were higher, which may be the main targets of SIGI. Then, the effect of SIGI was confirmed via functional experiments on invasion, migration, and adhesion assay, and the effect involved changes in the expressions of p-AKT, MMP2 and MMP13. Finally, combined with AKT activator (SC79) and inhibitor (MK2206), we further confirmed that SPV inhibits GBM invasion through AKT phosphorylation. Conclusions: This study provides valuable and an expected point of view into the regulation of AKT phosphorylation and inhibition of GBM invasion by SPV.

Exploring the prognostic value and potential therapeutic strategies of MS4A6A in glioblastoma: A comprehensive analysis of single-cell and multi-omics data.

Glioblastoma (GBM) is a highly aggressive and treatment-resistant malignancy that poses a significant challenge in modern medicine. Despite advances in surgical resection, radiotherapy and chemotherapy, complete eradication of GBM remains elusive due to its diffuse invasion into the brain parenchyma and propensity for recurrence. The tumour microenvironment (TME), particularly macrophages, has emerged as a critical player in GBM progression, invasion and metastasis. In the immune microenvironment of glioma, MS4A6A exhibits unique expression characteristics in macrophages. This study aimed to investigate the potential role of MS4A6A, a gene associated with aging and neurodegenerative diseases, in GBM and its potential as a prognostic biomarker and therapeutic target.

Bufotalin Induces Oxidative Stress-Mediated Apoptosis by Blocking the ITGB4/FAK/ERK Pathway in Glioblastoma.

Bufotalin (BT), a major active constituent of Chansu, has been found to possess multiple pharmacological activities. Although previous studies have shown that BT could inhibit the growth of glioblastoma (GBM), the safety of BT in vivo and the potential mechanism are still unclear. We conducted a systematic assessment to investigate the impact of BT on GBM cell viability, migration, invasion, and colony formation. Furthermore, in vivo results were obtained to evaluate the effect of BT on tumor growth. The preliminary findings of our study demonstrate the effective inhibition of GBM cell growth and subcutaneous tumor development in mice by BT, with tolerable levels of tolerance observed. Mechanistically, BT treatment induced mitochondrial dysfunction, bursts of reactive oxygen species (ROS), and subsequent cell apoptosis. More importantly, proteomic-based differentially expressed proteins analysis revealed a significant downregulation of integrin β4 (ITGB4) following BT treatment. Furthermore, our evidence suggested that the ITGB4/focal adhesion kinase (FAK)/extracellular signal-related kinase (ERK) pathway involved BT-induced apoptosis. Overall, our study demonstrates the anti-GBM effects of BT and elucidates the underlying mechanism, highlighting BT as a potential therapeutic option for GBM.

Glial-Cell-Line-Derived Neurotrophic Factor Promotes Glioblastoma Cell Migration and Invasion via the SMAD2/3-SERPINE1-Signaling Axis.

Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member 1 (SERPINE1) was a potential downstream gene of GDNF. Further experiments confirmed that SERPINE1 was highly expressed in GBM tissues and cells, and its levels of expression and secretion were enhanced by exogenous GDNF. SERPINE1 knockdown inhibited the migration and invasion of GBM cells promoted by GDNF. Mechanistically, GDNF increased SERPINE1 by promoting the phosphorylation of SMAD2/3. In vivo experiments demonstrated that GDNF facilitated GBM growth and the expressions of proteins related to migration and invasion via SERPINE1. Collectively, our findings revealed that GDNF upregulated SERPINE1 via the SMAD2/3-signaling pathway, thereby accelerating GBM cell migration and invasion. The present work presents a new mechanism of GDNF, supporting GBM development.

Biomimetic Nanosensitizer Potentiates Efficient Glioblastoma Gene-Radiotherapy through Synergistic Hypoxia Mitigation and PLK1 Silencing.

Postoperative radiotherapy currently stands as the cornerstone of glioblastoma (GBM) treatment. Nevertheless, low-dose radiotherapy has been proven ineffective for GBM, due to hypoxia in the GBM microenvironment, which renders the resistance to radiation-induced cell death. Moreover, the overexpression of the PLK1 gene in glioma cells enhances GBM proliferation, invasion, metastasis, and resistance to radiation. This study introduced a hybrid membrane-camouflaged biomimetic lipid nanosensitizer (CNL@miPA), which efficiently encapsulated gold nanoclusters (PA) and miR-593-5p by a chimeric membrane derived from lipids, cancer cells, and natural killer cells. CNL@miPA exhibited exceptional blood-brain barrier and tumor tissue penetration, effectively ameliorating hypoxia and synergizing with radiotherapy. By enabling prolonged miRNA circulation in the bloodstream and achieving high enrichment at the tumor site, CNL@miPA significantly suppressed tumor growth in combination treatment, thereby significantly extending the survival period of treated mice. Overall, the developed biomimetic nanosensitizer represented an efficient and multifunctional targeted delivery system, offering a novel strategy for gene-radiotherapy of GBM.

Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis

Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.

Bioinformatics Analysis Screening and Identification of Key Biomarkers and Drug Targets in Human Glioblastoma.

Glioblastoma is the most common type of brain cancer, with a prognosis that is unfortunately poor. Despite considerable progress in the field, the intricate molecular basis of this cancer remains elusive. The aim of this study was to identify genetic indicators of glioblastoma and reveal the processes behind its development. The advent and integration of supercomputing technology have led to a significant advancement in gene expression analysis platforms. Microarray analysis has gained recognition for its pivotal role in oncology, crucial for the molecular categorization of tumors, diagnosis, prognosis, stratification of patients, forecasting tumor responses, and pinpointing new targets for drug discovery. Numerous databases dedicated to cancer research, including the Gene Expression Omnibus (GEO) database, have been established. Identifying differentially expressed genes (DEGs) and key genes deepens our understanding of the initiation of glioblastoma, potentially unveiling novel markers for diagnosis and prognosis, as well as targets for the treatment of glioblastoma. This research sought to discover genes implicated in the development and progression of glioblastoma by analyzing microarray datasets GSE13276, GSE14805, and GSE109857 from the GEO database. DEGs were identified, and a function enrichment analysis was performed. Additionally, a protein-protein interaction network (PPI) was constructed, followed by module analysis using the tools STRING and Cytoscape. The analysis yielded 88 DEGs, consisting of 66 upregulated and 22 downregulated genes. These genes' functions and pathways primarily involved microtubule activity, mitotic cytokinesis, cerebral cortex development, localization of proteins to the kinetochore, and the condensation of chromosomes during mitosis. A group of 27 pivotal genes was pinpointed, with biological process analysis indicating significant enrichment in activities, such as division of the nucleus during mitosis, cell division, maintaining cohesion between sister chromatids, segregation of sister chromatids during mitosis, and cytokinesis. The survival analysis indicated that certain genes, including PCNA clamp-associated factor (PCLAF), ribonucleoside- diphosphate reductase subunit M2 (RRM2), nucleolar and spindle-associated protein 1 (NUSAP1), and kinesin family member 23 (KIF23), could be instrumental in the development, invasion, or recurrence of glioblastoma. The identification of DEGs and key genes in this study advances our comprehension of the molecular pathways that contribute to the oncogenesis and progression of glioblastoma. This research provides valuable insights into potential diagnostic and therapeutic targets for glioblastoma.

Inhibition of circular JUN prevents the proliferation and invasion of glioblastoma via miR-3064-IGFBP5 axis.

Glioblastoma (GBM) remains one of the most aggressive and lethal brain tumours, characterized by rapid progression and limited treatment options. This study investigated the regulatory roles of circular RNA circJUN, and its functional interaction with microRNA miR-3064 in GBM pathogenesis. We employed bioinformatic analyses and clinical sample validation to identify circJUN as a potential target in GBM. Subsequently, we engineered GBM cell lines with stable circJUN knockout or overexpression, and transfected them with miR-3064 mimic/inhibitor or IGFBP5 small interfering RNA (siRNA)/expression vector to elucidate the molecular mechanisms governing GBM proliferation and invasion. To investigate the invivo effects, xenograft tumour models were established in nude mice using engineered cells to assess the roles of circJUN in tumour growth regulation. Our analyses revealed significant overexpression of circJUN in GBM tissues compared to healthy controls, which strongly correlated with poor patient prognosis. Invitro and invivo experiments demonstrated that circJUN overexpression could enhance GBM cell proliferation and invasion. Mechanistic investigations uncovered EIF4A3 as an interacting factor of circJUN which promotes circJUN expression, and circJUN modulates miR-3064 activity to regulate the malignancy of GBM cells. Furthermore, we identified IGFBP5, a crucial regulator of cell growth, as a direct target of miR-3064, thereby establishing an additional layer of control over GBM proliferation and invasion. Our study unveils a complex regulatory network involving circJUN, miR-3064 and IGFBP5 in GBM pathogenesis, underscoring their potential as novel therapeutic targets for improving patient outcomes. Our findings not only contribute to the understanding of GBM biology but also pave the way for innovative therapeutic approaches in the management of this malignancy.

Human protoxin PSCA inhibits growth and invasion of glioblastoma

Human protoxin PSCA inhibits growth and invasion of glioblastoma

Dexmedetomidine inhibits the migration, invasion, and glycolysis of glioblastoma cells by lactylation of c-myc

ABSTRACT Background Glioblastoma (GBM) is a brain tumor with poor prognosis. Dexmedetomidine (Dex) regulates the biological behaviors of tumor cells to accelerate or decelerate cancer progression. Objective We investigated the effects of Dex on the migration, invasion, and glycolysis in GBM. Methods The concentration of Dex was determined using the cell counting kit-8 assay. The impacts of Dex on biological behaviors of GBM cells were assessed using Transwell assay, XF96 extracellular flux analysis, and western blot. The expression of c-Myc was examined using reverse transcription-quantitative polymerase chain reaction. The lactylation or stability of c-Myc was measured by western blot after immunoprecipitation or cycloheximide treatment. Results We found that Dex (200 nM) inhibited GBM cell viability, migration, invasion, and glycolysis. C-Myc was highly expressed in GBM cells and was decreased by Dex treatment. Moreover, Dex suppressed lactylated c-Myc levels via suppressing glycolysis, thereby reducing the protein stability of c-Myc. Sodium lactate treatment abrogated the effects of Dex on the biological behaviors of GBM cells. Conclusion Dex suppressed the migration, invasion, and glycolysis of GBM cells via inhibiting lactylation of c-Myc and suppressing the c-Myc stability, suggesting that Dex may be a novel therapeutic drug for GBM treatment.

B cell-based therapy produces antibodies that inhibit glioblastoma growth.

Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the BVax (B cell-based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of BVax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that BVax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by BVax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.

The Pattern of Copper Release in Copper‐Based Nanoparticles Regulates Tumor Proliferation and Invasiveness in 3D Culture Models

Cancer is a leading cause of death worldwide. Glioblastoma (GBM) is a major challenge in oncology due to its highly invasive nature and limited treatment options. GBM's aggressive migration beyond tumor margins and rapid tumor growth hinders success in patient treatment. Localized therapeutic delivery, such as the use of transition metals like copper, is highlighted as a novel therapeutic agent for many potential biomedical applications. Herein, it is aimed to study the effects of Cu release on the proliferation and invasiveness of cancer cells. To this end, novel copper‐based nanostructures with different release patterns are designed. Using a complex 3D cell culture model to mimic the tumor microenvironment, it is shown that different patterns of copper ion release have a strong impact on GBM progression and invasiveness. The findings highlight the importance of optimizing localized copper release patterns to tailor different tumor treatment strategies. They also show the potential and suitability of 3D microchips as instruments to study the behavior of tumor spheroids. In spite of their limitations, these 3D microdevices enable a controlled and close monitoring of the influence of environmental factors (such as the presence of Cu ions) on the proliferation and invasiveness of the cells, with a better approach to reality compared to 2D models and with a more controlled environment, compared to an in vivo model.

Up-regulation of LPCAT1 is correlated with poor prognosis and promotes tumor progression in glioblastoma.

Glioblastoma (GBM) is a cancer with high malignancy because of its rapid proliferation and high metastatic ability. LPCAT1 is reported to play a tumor-promoting role in multiple cancers, but its precise molecular mechanism in GBM remains to be further explored. We aim to explore the biological role of LPCAT1 in GBM. In this study, the expression of LPCAT1 and its correlation with clinicopathological characteristics of GBM patients were analyzed based on The Cancer Genome Atlas (TCGA) dataset. Kaplan-Meier approach was adopted for plotting survival curves for patients showing different expression levels of LPCAT1. Meanwhile, LPCAT1 expression within 50 GBM tumor tissues and 30 non-tumor clinical samples was analyzed by qRT-PCR and western blot assays, respectively. Later, LPCAT1's effect on GBM tumorigenesis was analyzed in vivo and in vitro by CCK8, EdU proliferation, clone forming, scratch, TUNEL assays, and subcutaneous xenograft experiments. As a result, LPCAT1 expression elevated within GBM tumor tissues and cells. Overexpression of LPCAT1 enhanced GBM cell growth, invasion and migration, while accelerating cell cycle progression. LPCAT1 silencing significantly inhibited cell motility and proliferation in vivo and in vitro, and arrested U251 cells at G0/G1 phase. Moreover, LPCAT1 might play a role in GBM progression by activating the p-AKT-MYC signaling pathway. LPCAT1 activated AKT, which were synchronously up-regulated MYC to accelerate cancer progression. Knockdown of LPCAT1 induced the opposite changes to repress the viability and motility of GBM cells. LPCAT1 contributed to the progression of GBM by participating in the p-AKT-MYC axis.

Microtubule-associated NAV3 regulates invasive phenotypes in glioblastoma cells.

Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule-associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient-derived glioma stem-like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior.

The microenvironmental factors induced invasive tumor cells in glioblastoma

Glioblastoma (GBM) cells have the potential to switch from being “proliferative cells” to peritumoral “invasive cells”. Peritumoral GBM cells have highly invasive properties that allow them to survive surgery, leading to recurrence. The mechanisms underlying the manner in which the tumor microenvironment (TME) regulates the invasiveness of GBM remain unclear. Single-cell RNA sequencing analysis revealed heterogeneity in GBM cells, microglia and macrophages. In this study, the Oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) expression indicated higher invasiveness in core GBM cells. Under environmental stress, the expression of OSMR and LIFR were up-regulated with the effect of hypoxic, acidic, and low-glucose conditions in vitro. Functional experiments revealed that TME stress significantly influences the proliferation, migration and invasion of GBM cells. The differences in core/peripheral TMEs in GBM affected the invasive properties, indicating the significant role of OSMR expression within the TME in tumor progression and postoperative therapy.

Triggering of endoplasmic reticulum stress via ATF4-SPHK1 signaling promotes glioblastoma invasion and chemoresistance

Despite advances in therapies, glioblastoma (GBM) recurrence is almost inevitable due to the aggressive growth behavior of GBM cells and drug resistance. Temozolomide (TMZ) is the preferred drug for GBM chemotherapy, however, development of TMZ resistance is over 50% cases in GBM patients. To investigate the mechanism of TMZ resistance and invasive characteristics of GBM, analysis of combined RNA-seq and ChIP-seq was performed in GBM cells in response to TMZ treatment. We found that the PERK/eIF2α/ATF4 signaling was significantly upregulated in the GBM cells with TMZ treatment, while blockage of ATF4 effectively inhibited cell migration and invasion. SPHK1 expression was transcriptionally upregulated by ATF4 in GBM cells in response to TMZ treatment. Blockage of ATF4-SPHK1 signaling attenuated the cellular and molecular events in terms of invasive characteristics and TMZ resistance. In conclusion, GBM cells acquired chemoresistance in response to TMZ treatment via constant ER stress. ATF4 transcriptionally upregulated SPHK1 expression to promote GBM cell aggression and TMZ resistance. The ATF4-SPHK1 signaling in the regulation of the transcription factors of EMT-related genes could be the underlying mechanism contributing to the invasion ability of GBM cells and TMZ resistance. ATF4-SPHK1-targeted therapy could be a potential strategy against TMZ resistance in GBM patients.

PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration

Invasion and migration are the key hallmarks of cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of glioblastoma cells in previous studies. However, the effects of PRMT6 on glioblastoma cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces glioblastoma cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of glioblastoma cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation mark (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in glioblastoma cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of glioblastoma cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate glioblastoma cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting glioblastoma cell invasion and migration.