Abstract
Abstract The C terminal binding proteins (CtBP) 1 and 2 are a family of transcriptional co-repressors overexpressed in a variety of cancers, and are frequently associated with poor prognosis and chemoresistance. CtBP has also been characterized in cell culture models as drivers of migration/invasion and epithelial-mesenchymal transition. CtBP mediates its transcriptional corepressor activity via its dehydrogenase domain, and inhibition of this domain interferes with CtBP oncogenic functions. The role of CtBP in APC mutant neoplasia remains obscure even though APC is responsible for degradation of both β-catenin and CtBP in suppressing colorectal tumorigenesis. Our prior work demonstrates that CtBP proteins can be effectively therapeutically targeted with substrate analogues of their intrinsic dehydrogenase domains. We now observe that pharmacologic inhibition of CtBP using either the 1st generation inhibitor 2-keto-4-methylthiobutyrate (MTOB) or the 2nd generation inhibitor hydroxyimino-3-phenylpropanoic acid (HIPP) significantly reduces the burden of intestinal polyps in the Apcmin mouse model of the human cancer predisposition syndrome Familial Adenomatous Polyposis. The number of intestinal polyps in mice with CtBP2 inhibitors were significantly lower (21 polyps/mouse for MTOB, 15 polyps/mouse for HIPP) as compared with vehicle treated mice (45 polyps/mouse) with a P value <0.0001. Pointing to the anti-neoplastic mechanism of MTOB and HIPP, polyps that did grow in MTOB or HIPP treated mice demonstrated robust downregulation of β catenin and Ctbp2 proteins. This observation points to the role of Ctbp2 as a putative driver oncogene that can be therapeutically targeted in vivo. In addition, CtBP2 has been reported to play an important role in human colon cancer stem cells via its interaction with the transcription factor TCF4 on chromatin. We now show that inhibiting CtBP with HIPP or HIPP analogues attenuates CtBP2 protein levels in colon cancer stem cells with resultant decreased expression of CtBP transcriptional target genes, such as the motility/invasion regulator TIAM1, and c-MYC, a known driver of the cancer stem cell phenotype. Moreover, colonospheres treated with CtBP inhibitor showed downregulation of cancer stem cell markers CD133 and c-MYC, as compared with vehicle treatment. Flow cytometry analysis of intestinal epithelium from Apcmin mice treated with CtBP inhibitor vs. vehicle indicated a significant reduction in CD133+/CXCR4+ cells that are associated with a tumor initiating cell phenotype. Our data demonstrate that CtBP inhibition may reduce colon neoplasia via downregulation of c-MYC and the cancer stem cell/tumor initiating cell compartment, and that CtBP is a promising and novel target for therapy in colon cancer. Citation Format: Ayesha T. Chawla, Agnes Cororaton, Rashmi Seth, Barbara Szomju, Evan T. Sumner, Steven R. Grossman. Therapeutic targeting of C-terminal binding protein: a key dependency for polyposis and cancer stem cell activity in APC mutant neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3901. doi:10.1158/1538-7445.AM2017-3901
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