title: 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.affiliation: Cancer Preventive Material Development Research Center, Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea. seokgeun@khu.ac.kr
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Keetae
authors.initials: K
authors.lastname: Kim
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Jung Kyoung
authors.initials: JK
authors.lastname: Choi
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Eric L
authors.initials: EL
authors.lastname: Howlett
authors.forename: Hyun Yong
authors.initials: HY
authors.lastname: Jeon
authors.forename: Zhao Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Dong-Chul
authors.initials: DC
authors.lastname: Kang
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D050882:CREB-Binding Protein / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D027342:Excitatory Amino Acid Transporter 2; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D051381:Rats; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C493397:SLC1A2 protein, human; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D018698:Glutamic Acid; D050882:CREB-Binding Protein; C494363:CREBBP protein, human