CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid

In ulcerative colitis (UC), Fusobacterium varium is significantly detected in patients' mucosa, and butyric acid (BA), abundantly produced by the bacterium, activates the p53 system and induces epithelial apoptosis, as we previously reported. However, factors active in the link between BA and p53 have yet to be clarified. Here, we identified a gene activated by BA specifically in UC-associated cancer cell lines and ascertained the mechanism of its activation of p53.

cDNA microarray analysis based on the Percellome (per cell normalization) method was performed on BA-stimulated UC-associated cancers and sporadic colorectal cancer cell lines under conditions mimicking colonic epithelium UC. For validation of microarray results, molecular, biochemical, and histopathological analyses were performed.

We found the CBP/p300-interacting transactivator with glutamic acid/asparagine-rich carboxy-terminal domain 2 (CITED2) to be specifically upregulated in UC-associated cancer cell lines by BA treatment, at both mRNA and protein expression levels. CITED2 could be shown to induce p53 acetylation and p53-dependent apoptosis, accompanied by binding of CBP/p300. BA-dependent apoptosis was suppressed by an inhibitor of monocarboxylate transporter-1 and an siRNA for p53. In inflammatory foci of UC, histologically evident inflammatory activity and CITED2 expression were significantly correlated.

CITED2 was identified as UC-associated protein by cDNA microarray based on the Percellome method under UC-mimicking conditions in vitro. CITED2 activation may induce mucosal apoptosis and erosion by activating p53 and thus play a critical role in linking enteric bacteria with mucosal inflammation in UC.