Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia


Overexpression of the transcriptional coregulators C-terminal binding proteins 1 and 2 (CtBP1 and 2) occurs in many human solid tumors and is associated with poor prognosis. CtBP modulates oncogenic gene expression programs and is an emerging drug target, but its oncogenic role is unclear. Consistent with this oncogenic potential, exogenous CtBP2 transformed primary mouse and human cells to anchorage independence similarly to mutant H-Ras. To investigate CtBP’s contribution to in vivo tumorigenesis, Apcmin/+ mice, which succumb to massive intestinal polyposis, were bred to Ctbp2+/− mice. CtBP interacts with adenomatous polyposis coli (APC) protein, and is stabilized in both APC-mutated human colon cancers and Apcmin/+ intestinal polyps. Ctbp2 heterozygosity increased the median survival of Apcmin/+ mice from 21 to 48 weeks, and reduced polyp formation by 90%, with Ctbp2+/− polyps exhibiting reduced levels of β-catenin and its oncogenic transcriptional target, cyclin D1. CtBP’s potential as a therapeutic target was studied by treating Apcmin/+ mice with the CtBP small-molecule inhibitors 4-methylthio-2-oxobutyric acid and 2-hydroxy-imino phenylpyruvic acid, both of which reduced polyposis by more than half compared with vehicle treatment. Phenocopying Ctbp2 deletion, both Ctbp inhibitors caused substantial decreases in the protein level of Ctbp2, as well its oncogenic partner β-catenin, and the effects of the inhibitors on CtBP and β-catenin levels could be modeled in an APC-mutated human colon cancer cell line. CtBP2 is thus a druggable transforming oncoprotein critical for the evolution of neoplasia driven by Apc mutation.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3


  1. Turner J, Crossley M . The CtBP family: enigmatic and enzymatic transcriptional co-repressors. BioEssays News Rev Mol Cell Dev Biol 2001; 23: 683–690.

    CAS  Article  Google Scholar 

  2. Chinnadurai G . The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res 2009; 69: 731–734.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Di L-J, Byun JS, Wong MM, Wakano C, Taylor T, Bilke S et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 2013; 4: 1449.

    Article  PubMed  Google Scholar 

  4. Zhang C, Gao C, Xu Y, Zhang Z . CtBP2 could promote prostate cancer cell proliferation through c-Myc signaling. Gene 2014; 546: 73–79.

    CAS  Article  PubMed  Google Scholar 

  5. Barroilhet L, Yang J, Hasselblatt K, Paranal RM, Ng S-K, Rauh-Hain JA et al. C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors. Oncogene 2013; 32: 3896–3903.

    CAS  Article  PubMed  Google Scholar 

  6. Straza MW, Paliwal S, Kovi RC, Rajeshkumar B, Trenh P, Parker D et al. Therapeutic targeting of C-terminal binding protein in human cancer. Cell Cycle 2010; 9: 3740–3750.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Kovi RC, Paliwal S, Pande S, Grossman SR . An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis. Cell Death Differ 2010; 17: 513–521.

    CAS  Article  PubMed  Google Scholar 

  8. Grooteclaes M, Deveraux Q, Hildebrand J, Zhang Q, Goodman RH, Frisch SM . C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs. Proc Natl Acad Sci USA 2003; 100: 4568–4573.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Paliwal S, Kovi RC, Nath B, Chen Y-W, Lewis BC, Grossman SR . The alternative reading frame tumor suppressor antagonizes hypoxia-induced cancer cell migration via interaction with the COOH-terminal binding protein corepressor. Cancer Res 2007; 67: 9322–9329.

    CAS  Article  PubMed  Google Scholar 

  10. Paliwal S, Ho N, Parker D, Grossman SR . CtBP2 Promotes Human Cancer Cell Migration by Transcriptional Activation of Tiam1. Genes Cancer 2012; 3: 481–490.

    PubMed  PubMed Central  Google Scholar 

  11. Korwar S, Morris BL, Parikh HI, Coover RA, Doughty TW, Love IM et al. Design, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP). Bioorg Med Chem 2016; 24: 2707–2715.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Hahn WC, Weinberg RA . Rules for making human tumor cells. N Engl J Med 2002; 347: 1593–1603.

    CAS  Article  PubMed  Google Scholar 

  13. Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A et al. APC mutations in sporadic colorectal tumors: A mutational ‘hotspot’ and interdependence of the ‘two hits’. Proc Natl Acad Sci 2000; 97: 3352–3357.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Groden J, Gelbert L, Thliveris A, Nelson L, Robertson M, Joslyn G et al. Mutational analysis of patients with adenomatous polyposis: identical inactivating mutations in unrelated individuals. Am J. Hum. Genet 1993; 52: 263–272.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992; 256: 668–670.

    CAS  Article  PubMed  Google Scholar 

  16. Phelps RA, Chidester S, Dehghanizadeh S, Phelps J, Sandoval IT, Rai K et al. A two step model for colon adenoma initiation and progression caused by APC loss. Cell 2009; 137: 623–634.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Nadauld LD, Phelps R, Moore BC, Eisinger A, Sandoval IT, Chidester S et al. Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases. J Biol Chem 2006; 281: 37828–37835.

    CAS  Article  PubMed  Google Scholar 

  18. Hildebrand JD, Soriano P . Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development. Mol Cell Biol 2002; 22: 5296–5307.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Yekkala K, Baudino TA . Inhibition of intestinal polyposis with reduced angiogenesis in ApcMin/+ mice due to decreases in c-Myc expression. Mol Cancer Res 2007; 5: 1296–1303.

    CAS  Article  PubMed  Google Scholar 

  20. Schneikert J, Brauburger K, Behrens J . APC mutations in colorectal tumours from FAP patients are selected for CtBP-mediated oligomerization of truncated APC. Hum Mol Genet 2011; 20: 3554–3564.

    CAS  Article  PubMed  Google Scholar 

  21. Paliwal S, Pande S, Kovi RC, Sharpless NE, Bardeesy N, Grossman SR . Targeting of C-Terminal Binding Protein (CtBP) by ARF Results in p53-Independent Apoptosis. Mol Cell Biol 2006; 26: 2360–2372.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


We thank LL for kindly donating BJ-blast cells and VSV-g/gag-pol retroviral expression vectors. We also thank SJ for his insight and thoughtful suggestions. SRG was funded by P30CA016059 from NCI and a Research Scholar Grant from ACS.

Author information

Authors and Affiliations


Corresponding author

Correspondence to S R Grossman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sumner, E., Chawla, A., Cororaton, A. et al. Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia. Oncogene 36, 4810–4816 (2017).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links