CtBP- an emerging oncogene and novel small molecule drug target: Advances in the understanding of its oncogenic action and identification of therapeutic inhibitors

Abstract

C-terminal Binding Proteins (CtBP) 1 and 2 are oncogenic transcriptional co-regulators overexpressed in many cancer types, with their expression level correlating to worse prognostic outcomes and aggressive tumor features. CtBP negatively regulates the expression of many tumor suppressor genes, while coactivating genes that promote proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal activity. In light of this evidence, the development of novel inhibitors that mitigate CtBP function may provide clinically actionable therapeutic tools. This review article focuses on the progress made in understanding CtBP structure, role in tumor progression, and discovery and development of CtBP inhibitors that target CtBP's dehydrogenase activity and other functions, with a focus on the theory and rationale behind the designs of current inhibitors. We provide insight into the future development and use of rational combination therapy that may further augment the efficacy of CtBP inhibitors, specifically addressing metastasis and cancer stem cell populations within tumors.

Keywords: C-terminal Binding Protein; CtBP; EMT; HIPP; MTOB; corepressor; dehydrogenase; oncogene; transcriptional co-regulator.

Figure 1.

(a) Domains of CtBP1- Role, functions and post-translational modification sites. R, E and H signify the catalytic triad within the CtBP dehydrogenase domain (b) Graphical representation of CtBP mediated co-repression, where CtBP nucleates a complex that bridges chromatin modifiers (including histone deacteylases [HDAC] and histone methyltransferases [HMT]) to specific DNA sites recognized by a DNA-interacting protein (DNA-IP) that encodes a PxDLS domain.

Figure 2.

Patterns of genetic alteration of CtBP1 and CtBP2 in human solid tumors. The Cancer Genome Atlas (TCGA) Project data were extracted using cBioportal (http://www.cbioportal.org/public-portal/), and show copy number alterations or mutations in TCGA tumor collections from 15 different cancer types.

Figure 3.

APC-dependent role of CtBP in the Wnt/ β-catenin pathway. In the presence of normal APC (APC-FL; left), CtBP participates in the destruction complex to sequester β-catenin (B-cat) and target it for proteasomal degradation. With mutant APC (APC-Mut/trunc; right), CtBP facilitates oligomerization and cytoplasmic sequestration of APC, promoting β-catenin release to the nucleus to induce downstream TCF/LEF mediated cell signaling, in which CtBP also plays a direct role as a coactivator at TCF target genes.

Figure 4.

CtBP reduces pyruvate in the presence of NADH to form lactate and NAD+.

Figure 5.

Structure of CtBP/substrate/coenzyme complex. (a) CtBP1 dehydrogenase domain structure (monomer) with domains indicated. Conformations of MTOB (light or dark blue) when interacting with (b) CtBP1 and (c) CtBP2 in presence of NAD+. (Reprinted with permission from Hilbert et al. Copyright 2014 John Wiley & Sons, Inc.)

Figure 6.

Ball and stick model representing interaction of CtBP1 with substrate MTOB, and substrate competitive inhibitors phenyl pyruvate (PPy) and HIPP (in stereo). (A) The hydrogen bond network of MTOB as reported in Hilbert et al (B) Phenylpyruvate (orange) possesses a similar hydrogen bond network to MTOB (orange dashes). (C) The non-canonical phenylpyruvate conformation (green) has a distinct hydrogen bond network (green dashes). Orientation of the carboxylate toward R266 of CtBP1 maximizes hydrogen bond potential as well as coulombic interactions (yellow dashes) with R97. (D) HIPP (cyan) forms a similar hydrogen bonding network (cyan dashes) to the non-canonical phenylpyruvate conformation, with the exception of losing the interaction with the nicotinamide ribose. (Reprinted with permission from Hilbert et al. Copyright 2015 American Chemical Society).