A C/EBPα-Wnt connection in gut homeostasis and carcinogenesis


  • J. Heuberger
  • U. Hill
  • S. Förster
  • K. Zimmermann
  • V. Malchin
  • A.A. Kühl
  • U. Stein
  • M. Vieth
  • W. Birchmeier
  • A. Leutz


  • Life Science Alliance


  • Life Sci Alliance 2 (1): e201800173


  • We explored the connection between C/EBPα (CCAAT/enhancer-binding protein α) and Wnt signaling in gut homeostasis and carcinogenesis. C/EBPα was expressed in human and murine intestinal epithelia in the transit-amplifying region of the crypts and was absent in intestinal stem cells and Paneth cells with activated Wnt signaling. In human colorectal cancer and murine APC(Min/+) polyps, C/EBPα was absent in the nuclear β-catenin-positive tumor cells. In chemically induced intestinal carcinogenesis, C/EBPα KO in murine gut epithelia increased tumor volume. C/EBPα deletion extended the S-phase cell zone in intestinal organoids and activated typical proliferation gene expression signatures, including that of Wnt target genes. Genetic activation of β-catenin in organoids attenuated C/EBPα expression, and ectopic C/EBPα expression in HCT116 cells abrogated proliferation. C/EBPα expression accompanied differentiation of the colon cancer cell line Caco-2, whereas β-catenin stabilization suppressed C/EBPα. These data suggest homeostatic and oncogenic suppressor functions of C/EBPα in the gut by restricting Wnt signaling.