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Molecular Pharmacology

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Research ArticleArticle

Pregnane X Receptor Represses HNF4α Gene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

Susumu Kodama, Yuichi Yamazaki and Masahiko Negishi
Molecular Pharmacology October 2015, 88 (4) 746-757; DOI: https://doi.org/10.1124/mol.115.099341
Susumu Kodama
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Yuichi Yamazaki
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Masahiko Negishi
Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Abstract

Upon treatment with the pregnane X receptor (PXR) activator rifampicin (RIF), human hepatocellular carcinoma HepG2-derived ShP51 cells that stably express PXR showed epithelial-mesenchymal transition (EMT)–like morphological changes and migration. Our recent DNA microarrays have identified hepatocyte nuclear factor (HNF) 4α and insulin-like growth factor-binding protein (IGFBP) 1 mRNAs to be downregulated and upregulated, respectively, in RIF-treated ShP51 cells, and these regulations were confirmed by the subsequent real-time polymerase chain reaction and Western blot analyses. Using this cell system, we demonstrated here that the PXR-HNF4α-IGFBP1 pathway is an essential signal for PXR-induced morphological changes and migration. First, we characterized the molecular mechanism underlying the PXR-mediated repression of the HNF4α gene. Chromatin conformation capture and chromatin immunoprecipitation (ChIP) assays revealed that PXR activation by RIF disrupted enhancer-promoter communication and prompted deacetylation of histone H3 in the HNF4α P1 promoter. Cell-based reporter and ChIP assays showed that PXR targeted the distal enhancer of the HNF4α P1 promoter and stimulated dissociation of HNF3β from the distal enhancer. Subsequently, small interfering RNA knockdown of HNF4α connected PXR-mediated gene regulation with the PXR-induced cellular responses, showing that the knockdown resulted in the upregulation of IGFBP1 and EMT-like morphological changes without RIF treatment. Moreover, recombinant IGFBP1 augmented migration, whereas an anti-IGFBP1 antibody attenuated both PXR-induced morphological changes and migration in ShP51 cells. PXR indirectly activated the IGFBP1 gene by repressing the HNF4α gene, thus enabling upregulation of IGFBP1 to change the morphology of ShP51 cells and cause migration. These results provide new insights into PXR-mediated cellular responses toward xenobiotics including therapeutics.

Footnotes

    • Received April 16, 2015.
    • Accepted July 23, 2015.
  • ↵1 Current affiliation: Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

  • ↵2 Current affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.

  • S.K. and Y.Y. contributed equally to this work.

  • This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences [Grant Z01-ES1005-01].

  • dx.doi.org/10.1124/mol.115.099341.

  • ↵Embedded ImageThis article has supplemental material available at mol.pharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 88 (4)
Molecular Pharmacology
Vol. 88, Issue 4
1 Oct 2015
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Research ArticleArticle

PXR-HNF4α-IGFBP1 Pathway as a Signal for Cell Migration

Susumu Kodama, Yuichi Yamazaki and Masahiko Negishi
Molecular Pharmacology October 1, 2015, 88 (4) 746-757; DOI: https://doi.org/10.1124/mol.115.099341

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Research ArticleArticle

PXR-HNF4α-IGFBP1 Pathway as a Signal for Cell Migration

Susumu Kodama, Yuichi Yamazaki and Masahiko Negishi
Molecular Pharmacology October 1, 2015, 88 (4) 746-757; DOI: https://doi.org/10.1124/mol.115.099341
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