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. Astrocyte elevated gene-1 (AEG-1) is an oncogene that is overexpressed in several types of human cancers, including more than 90% of brain tumors. In addition, AEG-1 promotes gliomagenesis, particularly in the context of tumor growth and invasion, 2 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 samples from glioma patients 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 samples from glioma patients showing 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.

• Authors: Seok-Geun Lee, Keetae Kim, Timothy P Kegelman, Rupesh Dash, Swadesh K Das, Jung Kyoung Choi, Luni Emdad, Eric L Howlett, Hyun Yong Jeon, Zhao Zhong Su, Byoung Kwon Yoo, Devanand Sarkar, Sung-Hoon Kim, Dong-Chul Kang, Paul B Fisher
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 20 Pg. 6514-23 (Oct 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21852380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Excitatory Amino Acid Transporter 2
• Glutamate Plasma Membrane Transport Proteins
• MTDH protein, human
• Membrane Proteins
• RNA-Binding Proteins
• SLC1A2 protein, human
• YY1 Transcription Factor
• YY1 protein, human
• Glutamic Acid
• CREB-Binding Protein
• CREBBP protein, human

Topics

• Animals
• Astrocytes (metabolism, pathology)
• Brain (metabolism)
• Brain Neoplasms (metabolism, pathology)
• CREB-Binding Protein (metabolism)
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Line, Tumor
• Excitatory Amino Acid Transporter 2
• Glioma (metabolism, pathology)
• Glutamate Plasma Membrane Transport Proteins (metabolism)
• Glutamic Acid (metabolism)
• Humans
• Membrane Proteins
• Nerve Degeneration (metabolism, pathology)
• Oncogenes
• Promoter Regions, Genetic
• RNA-Binding Proteins
• Rats
• YY1 Transcription Factor (metabolism)