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

Ayesha T Chawla; Agnes D Cororaton; Michael O Idowu; Priyadarshan K Damle; Barbara Szomju; Keith C Ellis; Bhaumik B Patel; Steven R Grossman

doi:10.18632/oncotarget.25784

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

Oncotarget. 2018 Aug 21;9(65):32408-32418. doi: 10.18632/oncotarget.25784.

Authors

Ayesha T Chawla¹, Agnes D Cororaton², Michael O Idowu^{3

4}, Priyadarshan K Damle², Barbara Szomju², Keith C Ellis^{4

5}, Bhaumik B Patel^{2

4

6}, Steven R Grossman^{2

4}

Affiliations

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 Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁶ Department of Medicine, Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA.

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^minCtbp2^+/- 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.

Keywords: adenomatous polyposis; c terminal binding protein; tumor initiating cells.

Abstract

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