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

// Ayesha T. Chawla 1 , Agnes D. Cororaton 2 , Michael O. Idowu 3, 4 , Priyadarshan K. Damle 2 , Barbara Szomju 2 , Keith C. Ellis 4, 6 , Bhaumik B. Patel 2, 4, 5 and Steven R. Grossman 2, 4 1 VCU Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA 2 Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA 3 Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA 4 VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA 5 Department of Medicine, Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA 6 Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA Correspondence to: Steven R. Grossman, email: steven.grossman@vcuhealth.org Keywords: c terminal binding protein; adenomatous polyposis; tumor initiating cells Received: May 19, 2018      Accepted: June 19, 2018      Published: August 21, 2018 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.