Research Highlights

Colonic mucosa: At the core of colitis and carcinogenesis

LacZ staining of C3GnT^+/+ and C3GnT^–/– colonic tissues. Copyright © 2007 by the Rockefeller University Press.

Intestinal epithelia are covered by heavily O-glycosylated mucins, which form the mucosal lining. Sicknesses such as inflammatory bowel disease and cancer occur when the intestinal barrier function is disrupted. Likewise, changes in mucin O-glycosylation have been reported both for colorectal cancer and ulcerative colitis, yet the precise contribution of individual glycan structures and glycosyltransferase activities to pathogenesis is still not entirely clear. Now in the Journal of Experimental Medicine, An and colleagues show that disruption of core31,3-N-acetylglucosaminyltransferase (C3GnT) has severe physiological consequences for the colonic epithelium.

C3GnT forms the mucin-type core3 O-glycan by transferring N-acetylglucosamine (GlcNAc) to the Tn antigen glycan, serine- or threonine-linked N‑acetylgalactosamine (GalNAc). The authors generated C3GnT^-/- mice, which developed normally except for a lack of core3 structures in the colonic mucosa. Instead, Tn antigen was exposed which indicates that synthesis of core3 O-glycans specifically requires C3GnT.

The authors discovered that a lack of core3 structures led to a reduction of MUC2 mucin production in the colon. Furthermore, cellular staining showed that the integrity of the mucosal layer was impaired in C3GnT^-/- mice. Therefore, core3 O-glycan, and by extension the activity of C3GnT is likely required for the normal generation of the epithelial mucus.

C3GnT^-/-mice were highly susceptible to induced colitis accompanied by the expression of proinflammatory cytokines. Furthermore, C3GnT^-/- mice developed tumors much more quickly than their wild-type counterparts following exposure to carcinogen. The increased susceptibility to tumorigenesis in the knockout mice could be due to the increased epithelial cell proliferation and heightened expression of Wnt signaling pathway molecules — central players in colon carcinogenesis — found in C3GnT^-/- mice.

The results of An et al. show that disruption of normal colonic O-glycosylation has repercussions on mucus production, epithelial cell proliferation and intracellular signaling, which eventually lead to colitis and carcinogenesis. Future studies may shed light on the observed connection between a lack of core3 O-glycans and enhanced Wnt signaling. Interestingly, the C3GnT appears to be the only enzyme synthesizing core3 structures, while other glycostransferases often build families with related structures and functions. Studies of mice with genetic deletions of glycosyltransferases akin to C3GnT may be particularly valuable for the delineation of individual glycan functions. It will be interesting to determine if a lack of C3GnT or other glycosyltransferase activity could underpin the reported link between colitis and colon carcinogenesis in humans.

Author: Mirko von Elstermann