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Regulation of N-Myc downstream regulated gene 2 by bile acids

Cédric Langhi1, Elena Pedraz-Cuesta, Yolanda Donate

  • 1Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and the Institute of Biomedicine of the University of Barcelona, Barcelona E-08028, Spain.

Biochemical and Biophysical Research Communications
|April 2, 2013
PubMed

Insights

Bile acid chenodeoxycholic acid (CDCA) and a synthetic farnesoid X receptor (FXR) agonist increase the expression of the tumor suppressor N-Myc downstream regulated gene 2 (NDRG2). This finding links bile acid metabolism to cancer. Keywords: bile acid, CDCA, FXR, NDRG2, cancer.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cancer Research

Background:

  • Bile acids play crucial roles in metabolism and have been implicated in cancer.
  • The farnesoid X receptor (FXR) is a key regulator of bile acid metabolism.
  • N-Myc downstream regulated gene 2 (NDRG2) is a known tumor suppressor.

Purpose of the Study:

  • To investigate the effect of bile acids and FXR on NDRG2 expression.
  • To identify the regulatory mechanisms linking FXR and NDRG2.
  • To explore the physiological relevance of NDRG2 regulation by bile acids.

Main Methods:

  • Treatment of human hepatoma cells and primary hepatocytes with CDCA and GW4064.
  • FXR knockdown and overexpression studies.
  • Identification of a FXR-response element in gene introns.
  • In vivo studies in mice treated with GW4064.

Main Results:

  • CDCA and GW4064 robustly induced NDRG2 expression.
  • FXR knockdown abolished CDCA-induced NDRG2 expression; FXR overexpression enhanced it.
  • A FXR-response element was identified in human and murine NDRG2 genes.
  • NDRG2 expression increased in mouse liver and kidney upon GW4064 administration.

Conclusions:

  • NDRG2 is a novel bile acid-regulated gene.
  • FXR directly regulates NDRG2 expression.
  • This discovery provides new insights into the link between bile acid metabolism and cancer.

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