Abstract 2052: The transcriptional co-regulator and emerging cancer drug target C-terminal binding protein (CtBP) is a transforming oncogene

Abstract

Abstract The paralogous C-terminal binding proteins (collectively CtBP) 1 and 2 are evolutionarily conserved transcriptional co-regulators which demonstrate oncogene-like properties such as allowing for the progression of EMT and cellular invasion/migration, and supporting cellular survival through suppression of tumor suppressors (PTEN, p16, E-cadherin, BRCA-1) and pro-apoptotic genes (Bik, Puma, Noxa). Overexpression of CtBP is found in colon, ovarian, breast, and prostate cancers, and often correlates with loss of the tumor suppressors ARF and APC and with poorer prognosis for the patient. CtBP is also an emerging cancer drug target, encoding a dehydrogenase domain that can be targeted with small molecule inhibitors to kill cancer cells. CtBP appears to fit the criteria for a driver oncogene, though has never been fully characterized as such. To investigate the hypothesis that CtBP is a transforming oncogene, we subjected CtBP2 to multiple assays for cellular oncogenic activity including loss of contact inhibition, invasion, and anchorage independent growth. Previously immortalized NIH 3T3 mouse fibroblasts expressing CtBP2 or mutant H-Ras as a positive control were analyzed for focus formation, Matrigel-invasion, and soft agar colony formation. Consistent with the hypothesis that CtBP exhibits properties of an oncogene, CtBP2 potently induced focus formation, Matrigel-invasion, and soft agar colony formation with similar potency to oncogenic mutant H-Ras. Moreover, CtBP2 cooperated with the adenovirus E1A oncoprotein but not H-Ras to transform primary mouse embryonic fibroblasts (MEFs). Taken together, the 3T3 and MEF transformation data suggest CtBP2 acts as a “Ras-like” oncogene in rodent cell transformation assays. Previous research from our lab has shown that CtBP's ability to induce migration in HCT116 cells depends in part on its activation of T-cell lymphoma invasion and metastasis 1 (Tiam1). Work is ongoing to characterize critical downstream targets for CtBP's transforming activity. Targeting CtBP and its dehydrogenase domain in cancers where the protein is found to be overexpressed, or where its regulators, ARF and APC are found to be inactive, could lead to a therapeutic approach specific for an emerging driver oncogene. Citation Format: Evan T. Sumner, Steven R. Grossman. The transcriptional co-regulator and emerging cancer drug target C-terminal binding protein (CtBP) is a transforming oncogene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2052. doi:10.1158/1538-7445.AM2015-2052