Abstract
C-terminal binding protein 2 (CtBP2) drives intestinal polyposis in the Apc min 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 Apc mutated human neoplasia. Tumor initiating cell (TIC) populations were substantially decreased in Apc min Ctbp2+/- intestinal epithelia. Moreover, normally nuclear Ctbp2 was mislocalized to the cytoplasm of intestinal crypt stem cells in Ctbp2+/- mice, both Apc min and wildtype, correlating with low/absent CD133 expression in those cells, and possibly explaining the lower burden of polyps in Apc min Ctbp2+/- mice. The CtBP inhibitor 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) also robustly downregulated TIC populations and significantly decreased intestinal polyposis in Apc min mice. We have therefore demonstrated a critical link between polyposis, intestinal TIC’s and Ctbp2 gene dosage or activity, supporting continued efforts targeting CtBP in the treatment or prevention of Apc mutated neoplasia.
Highlights
Sporadic colon cancer is frequently characterized by mutation of the APC tumor suppressor, while autosomal dominant inheritance of a mutant APC allele, as in Familial Adenomatous Polyposis (FAP), results in early onset massive colonic polyposis that uniformly progresses to colorectal cancer unless prophylactic total colectomy is performed [1]
We show that Ctbp2 loss or inhibition with 4-Cl-hydroxyimino-3-phenylpropionic acid (HIPP) both reduce normal stem cell and Tumor initiating cell (TIC) populations in Apc min/+ (Apc min) intestine, with a surprising finding of Ctbp2 protein misolocalization to the cytoplasm of stem cells and tumor initiating cells (TIC’s) when haploinsufficient
To understand the role of Ctbp2 in TIC activity induced by Apc mutated neoplasia, we first compared CD44+/CD24+ as well as CD133+/CXCR4+ populations in small intestinal epithelia obtained from Apc, min/+ Ctbp2 +/- Apc, min/+ wildtype and Ctbp2 +/- mice (Figure 1A, Supplementary Figure 1A)
Summary
Sporadic colon cancer is frequently characterized by mutation of the APC tumor suppressor, while autosomal dominant inheritance of a mutant APC allele, as in Familial Adenomatous Polyposis (FAP), results in early onset massive colonic polyposis that uniformly progresses to colorectal cancer unless prophylactic total colectomy is performed [1]. We show that Ctbp loss or inhibition with 4-Cl-HIPP both reduce normal stem cell and TIC populations in Apc min intestine, with a surprising finding of Ctbp protein misolocalization to the cytoplasm of stem cells and TIC’s when haploinsufficient. This mislocalization could explain the profound effect of Ctbp haploinsufficiency on polyp number and survival in Apc min mice and supports further therapeutic development of CtBP as a target in APC mutated neoplasia
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