title: AEG-1 regulates retinoid X receptor and inhibits retinoid signaling.
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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Srivastava
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Chadia L
authors.initials: CL
authors.lastname: Robertson
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Devaraja
authors.initials: D
authors.lastname: Rajasekaran
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Gil
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhere
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia. dsarkar@vcu.edu.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D008822:Mice, Transgenic; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D047488:Retinoid X Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D014212:Tretinoin