An intestinal stem cell niche in Apc mutated neoplasia targetable by CtBP inhibition
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Ayesha T. Chawla1, Agnes D. Cororaton2, Michael O. Idowu3,4, Priyadarshan K. Damle2, Barbara Szomju2, Keith C. Ellis4,6, Bhaumik B. Patel2,4,5 and Steven R. Grossman2,4
1VCU Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA
2Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
3Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA
4VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
5Department of Medicine, Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA
6Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA
Steven R. Grossman, email: [email protected]
Keywords: c terminal binding protein; adenomatous polyposis; tumor initiating cells
Received: May 19, 2018 Accepted: June 19, 2018 Published: August 21, 2018
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.
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