AEG-1 regulates retinoid X receptor and inhibits retinoid signaling

Cancer Res. 2014 Aug 15;74(16):4364-77. doi: 10.1158/0008-5472.CAN-14-0421.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism*
  • Cell Differentiation / physiology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Heterografts
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Nude
  • Mice, Transgenic
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA-Binding Proteins
  • Retinoid X Receptors / antagonists & inhibitors
  • Retinoid X Receptors / genetics
  • Retinoid X Receptors / metabolism*
  • Retinoids / antagonists & inhibitors*
  • Retinoids / metabolism
  • Signal Transduction
  • Transfection
  • Tretinoin / pharmacology
  • Up-Regulation

Substances

  • Cell Adhesion Molecules
  • MTDH protein, human
  • Membrane Proteins
  • RNA-Binding Proteins
  • Retinoid X Receptors
  • Retinoids
  • Tretinoin