Astrocyte Elevated Gene 1 Interacts with Acetyltransferase p300 and c-Jun To Promote Tumor Aggressiveness

Abstract

Astrocyte elevated gene 1 (AEG-1) is an oncoprotein that strongly promotes the development and progression of cancers. However, the detailed underlying mechanisms through which AEG-1 enhances tumor development and progression remain to be determined. In this study, we identified c-Jun and p300 to be novel interacting partners of AEG-1 in gliomas. AEG-1 promoted c-Jun transcriptional activity by interacting with the c-Jun/p300 complex and inducing c-Jun acetylation. Furthermore, the AEG-1/c-Jun/p300 complex was found to bind the promoter of c-Jun downstream targeted genes, consequently establishing an acetylated chromatin state that favors transcriptional activation. Importantly, AEG-1/p300-mediated c-Jun acetylation resulted in the development of a more aggressive malignant phenotype in gliomas through a drastic increase in glioma cell proliferation and angiogenesis in vitro and in vivo. Consistently, the AEG-1 expression levels in clinical glioma specimens correlated with the status of c-Jun activation. Taken together, our results suggest that AEG-1 mediates a novel epigenetic mechanism that enhances c-Jun transcriptional activity to induce glioma progression and that AEG-1 might be a novel, potential target for the treatment of gliomas.

Pentraxin 3 Promotes Glioblastoma Progression by Negative Regulating Cells Autophagy

“…The PI3K/Art pathway and the NF-κB pathway activation can initiate JUN expression in head and neck cancer ( Chang et al, 2015 ). Factors like astrocyte elevated gene 1 ( Liu et al, 2017 ), microRNA-4476 ( Lin et al, 2020 ), 3-phosphoinositide dependent protein kinase 1 ( Luo et al, 2018 ) can also activate c-jun expression. Therefore, JUN participates in cells autophagy regulation by affecting PTX3 expression.…”

Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance

“…The activation of MAPK/ERK results in activation of the transcription factor AP-1, a heterodimer of Fos and Jun family proteins, and it was documented that AEG-1 knockdown results in a marked inhibition of AP-1 DNA binding in prostate cancer cells [ 196 ]. In glioma cells, it was documented that AEG-1 interacts with the c-Jun/p300 complex, inducing c-Jun acetylation and increased DNA binding with a resultant enhanced expression of the target genes and increase in cell proliferation and angiogenesis both in vitro and in vivo [ 207 ]. The activation of ERK by AEG-1 induced the phosphorylation of RXR, thereby inhibiting RXR function [ 132 ].…”

Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling

“…The expression of AEG-1 is often deregulated in solid tumors [ 41 ] and is closely linked to multiple oncogenic signaling pathways, including the Ha-Ras, PI3K/AKT, NF-κB, c-Myc, and Wnt/β-catenin pathways [ 11 , 12 , 18 , 29 ]. Protein-protein interaction mapping is important for understanding the oncogenic function of AEG-1 since AEG-1 interacts with various proteins including c-Jun, p300, NF-κB, IKKβ, AKT2, and SND1 to activate oncogenic signaling pathways [ 13 , 14 , 15 , 16 , 17 ]. Here, we report NCL as a novel AEG-1 interacting protein.…”

“…AEG-1 promotes the AKT-mediated survival signaling pathway, suggesting that the Ras-PI3K-AKT pathway is closely linked to the oncogenic function of AEG-1 via the activation of a positive feedback mechanism [ 12 ]. AEG-1 regulates genes involved in the migration and invasion of cancer cells by activating the NF-κB pathway [ 13 ] and interacting with various oncoproteins [ 13 , 14 , 15 , 16 , 17 ]. AEG-1 interacts with AKT2, increasing cell survival and proliferation via phosphorylation of AKT2 and GSK3β [ 16 ].…”