Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells

Huajun Han, Laurie A. Davidson, Yang Yi Fan, Jennifer S. Goldsby, Grace Yoon, Un Ho Jin, Gus A. Wright, Kerstin K. Landrock, Bradley R. Weeks, Rachel C. Wright, Clinton D. Allred, Arul Jayaraman, Ivan Ivanov, Jatin Roper, Stephen H. Safe, Robert S. Chapkin

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5+ stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal-specific AhR knockout increases basal stem cell and crypt injury-induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR-FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.

Original languageEnglish (US)
Article numbere104319
JournalEMBO Journal
Volume39
Issue number19
DOIs
StatePublished - Oct 1 2020
Externally publishedYes

Keywords

  • aryl hydrocarbon receptor
  • colon cancer
  • progenitor cells
  • stem cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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