Title: Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.
Authors: Han, Huajun; Davidson, Laurie A; Fan, Yang-Yi; Goldsby, Jennifer S; Yoon, Grace; Jin, Un-Ho; Wright, Gus A; Landrock, Kerstin K; Weeks, Bradley R; Wright, Rachel C; Allred, Clinton D; Jayaraman, Arul; Ivanov, Ivan; Roper, Jatin; Safe, Stephen H; Chapkin, Robert S
Published In EMBO J, (2020 10 01)
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.
PubMed ID: 32915464
MeSH Terms: Animals; Colon/metabolism*; Female; Forkhead Box Protein M1/genetics; Forkhead Box Protein M1/metabolism*; Gene Knockout Techniques; Humans; Male; Mice; Mice, Transgenic; Receptors, Aryl Hydrocarbon/deficiency*; Receptors, Aryl Hydrocarbon/metabolism; Signal Transduction*; Stem Cells/metabolism*