Oncogene AEG-1 Promotes Glioma-Induced Neurodegeneration by Increasing Glutamate Excitotoxicity

Abstract

Aggressive tumor growth, diffuse tissue invasion and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. AEG-1 is an oncogene overexpressed in multiple types of human cancers including >90% of brain tumors. AEG-1 also promotes gliomagenesis particularly in the context of tumor growth and invasion, two primary characteristics of glioma. In the present study, we investigated the contribution of AEG-1 to glioma-induced neurodegeneration. Pearson correlation coefficient analysis in normal brain tissues and glioma patient samples indicated a strong negative correlation between expression of AEG-1 and a primary glutamate transporter of astrocytes EAAT2. Gain and loss of function studies in normal primary human fetal astrocytes and T98G glioblastoma multiforme cells revealed that AEG-1 repressed EAAT2 expression at a transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter. In addition, AEG-1-mediated EAAT2 repression caused a reduction of glutamate uptake by glial cells, resulting in induction of neuronal cell death. These findings were also confirmed in glioma patient samples demonstrating that AEG-1 expression negatively correlated with NeuN expression. Taken together, our findings suggest that AEG-1 contributes to glioma-induced neurodegeneration, a hallmark of this fatal tumor, through regulation of EAAT2 expression.

Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

“…YY1 mediates the AEG-1-induced repression of EAAT2 (21). Therefore, the role and mechanism of YY1 in negatively regulating EAAT2 transcription were ascertained.…”

“…With respect to glutamate transporters, YY1 plays a role in EAAT1 (GLAST) repression as glutamate treatment increases YY1 DNA binding, decreasing glutamate uptake in chick Bergmann glia cells (20). YY1 has also been reported to regulate EAAT2 gene expression as astrocyte elevated gene 1 (AEG-1) is able to recruit YY1 to form a DNA binding complex to repress EAAT2 (21).…”

Embelin Induces Apoptosis in Human Glioma Cells Through Inactivating NF-κB

“…Whole cell lysates were prepared, and western blotting was performed as described (23). Primary antibodies for phospho-IκBα (1:1000), IκBα (1:1000), CASP3 (1:1000), c-CASP3 (1:1000), CASP8 (1:1000), c-CASP8 (1:1000), CASP9 (1:1000), c-CASP9 (1:1000), c-PARP (1:1000), XIAP (1:1000), Bcl-XL (1:1000), Bcl-2 (1:1000), CDK2 (1:1000), CDK4 (1:1000), cyclin D1 (1:1000), cyclin E (1:1000), AKT (1:1000), phospho-AKT (1:1000), ERK (1:1000), phospho-ERK (1:1000), c-Notch1 (1:500), p65 (1:1000), phospho-p65 (1:1000), p50 (1:1000), and phospho-p50 (1:1000) were used for immnuoblotting followed by horseradish peroxidase-conjugated antimouse IgG or anti-rabbit IgG (1:3000; Cell Signaling Biotechnology, Danvers, MA, USA) for 1 h and were detected using a chemiluminescence system (Corebio, Seoul, Republic of Korea).…”

“…For analyzing localization of p65, cells were plated in 8-well chamber slides and treated with 50 μM of embelin for 24 h. Then the cells were fixed and immunostaining was performed with rabbit polyclonal anti-p65 antibody (1:200) and Alexa Flour 488 goat anti-rabbit antibody (1:1000) and DAPI as described (23). The images were taken with the FluoView FV1000 confocal microscope (Olympus, Tokyo).…”

Multimodal Elucidation of Choline Metabolism in a Murine Glioma Model Using Magnetic Resonance Spectroscopy and 11C-Choline Positron Emission Tomography

“…However, also a decrease in the contralateral hemisphere is present resulting in an increase of the tumor-to-brain ratios. Possible explanations for this phenomenon could be different choline concentrations in the brain (24), accelerated aging (25,26) and glioma-induced neurodegenerative processes (27), reduced global cerebral blood flow (28), and ischemia (29). Doblas and colleagues have also observed significant variations and heterogeneity in different rodent gliomas, such as the F98 model (8.1 AE 12.4; ref.…”