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AEG-1 Regulates Retinoid X Receptor and Inhibits Retinoid Signaling
- Source :
- Cancer Research. 74:4364-4377
- Publication Year :
- 2014
- Publisher :
- American Association for Cancer Research (AACR), 2014.
-
Abstract
- Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)–mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. Cancer Res; 74(16); 4364–77. ©2014 AACR.
- Subjects :
- Cancer Research
medicine.drug_class
Retinoic acid
Mice, Nude
Mice, Transgenic
Tretinoin
Biology
Retinoid X receptor
Transfection
Article
Mice
Retinoids
chemistry.chemical_compound
medicine
Animals
Humans
Retinoid
Phosphorylation
Promoter Regions, Genetic
Retinoid X receptor alpha
organic chemicals
Liver Neoplasms
Membrane Proteins
RNA-Binding Proteins
Cell Differentiation
Retinoid X receptor gamma
Up-Regulation
Mice, Inbred C57BL
body regions
Retinoic acid receptor
HEK293 Cells
Retinoid X Receptors
Oncology
chemistry
Retinoic acid receptor alpha
Gene Knockdown Techniques
embryonic structures
Mice, Inbred CBA
Cancer research
Heterografts
Retinoid X receptor beta
Cell Adhesion Molecules
Signal Transduction
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....39b590e59fa2ebd8ecf4771454a48920