An intestinal stem cell niche in mutated neoplasia targetable by CtBP inhibition.

C-terminal binding protein 2 (CtBP2) drives intestinal polyposis in the mouse model of human Familial Adenomatous Polyposis. As CtBP2 is targetable by an inhibitor of its dehydrogenase domain, understanding CtBP2's role in adenoma formation is necessary to optimize CtBP-targeted therapies in mutated human neoplasia. Tumor initiating cell (TIC) populations were substantially decreased in intestinal epithelia. Moreover, normally nuclear Ctbp2 was mislocalized to the cytoplasm of intestinal crypt stem cells in mice, both and wildtype, correlating with low/absent CD133 expression in those cells, and possibly explaining the lower burden of polyps in Ctbp2 mice. The CtBP inhibitor 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) also robustly downregulated TIC populations and significantly decreased intestinal polyposis in mice. We have therefore demonstrated a critical link between polyposis, intestinal TIC's and gene dosage or activity, supporting continued efforts targeting CtBP in the treatment or prevention of mutated neoplasia.