The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target

Abstract

Transcriptional corepressor proteins have emerged as an important facet of cancer etiology. These corepressor proteins are often altered by loss- or gain-of-function mutations, leading to transcriptional imbalance. Thus, research directed at expanding our current understanding of transcriptional corepressors could impact the future development of new cancer diagnostics, prognostics, and therapies. In this review, our current understanding of the CtBP corepressors, and their role in both development and disease, is discussed in detail. Importantly, the role of CtBP1 overexpression in adult tissues in promoting the progression of multiple cancer types through their ability to modulate the transcription of developmental genes ectopically is explored. CtBP1 overexpression is known to be protumorigenic and affects the regulation of gene networks associated with "cancer hallmarks" and malignant behavior, including increased cell survival, proliferation, migration, invasion, and the epithelial-mesenchymal transition. As a transcriptional regulator of broad developmental processes capable of promoting malignant growth in adult tissues, therapeutically targeting the CtBP1 corepressor has the potential to be an effective method for the treatment of diverse tumor types. Although efforts to develop CtBP1 inhibitors are still in the early stages, the current progress and the future perspectives of therapeutically targeting this transcriptional corepressor are also discussed. Mol Cancer Ther; 16(6); 981-90. ©2017 AACR.

Figure 1. Molecular details of the rat CtBP1-S/E1A peptide interaction

(A) A domain organization map of CtBP1. Each domain and their corresponding amino acid ranges are listed below the linear map while the binding interfaces and their corresponding amino acid residues or ranges are listed above. (B) The crystal structure of the rat CtBP1-S dimer (blue and purple ribbons) in complex with the PIDLSKK E1A peptide (green) (PDB:1HL3) (18). The NADH cofactor is represented as orange sticks in the center of each CtBP1-S molecule. (C) An electrostatic surface representation of CtBP1-S at the peptide interface. The PIDLSKK peptide is shown as green sticks. (D) A surface representation of CtBP1-S highlighting the location of the two residues, V55 and A41 (orange). Mutation of these residues disrupts the ability of CtBP1-S to interact with E1A. (E) A sequence alignment of different dehydrogenase family members in the CtBP1 region that binds its transcription factor partners. The sequence alignment of CtBP family members and the two other dehydrogenases: lactate (LDH) and malate (MDH) dehydrogenases, was performed using Clustal Omega (122). Residues that make up the hydrophobic binding pocket are italicized, and those that are involved in hydrogen bonds are underlined.

Figure 2. The CtBP1 transcriptional co-repressor influences a number of Cancer Hallmarks to carry out its tumor-promoting functions

CtBP1 has been shown to play a role in five out of the six original cancer hallmarks and one of the two enabling characteristics, highlighting the potential importance of therapeutically targeting this transcriptional complex.

Figure 3. Chemical structures of the current compounds identified as inhibitors of CtBP1 transcriptional activity

(A) NSC95397 was discovered through high-throughput screening. (B) 2-keto-4-methylthiobutyrate (MTOB) was identified through screening known substrates of other dehydrogenases. (C) Phenylpyruvate and 2-hydroxyimino-3-phenylproanoic acid are MTOB derivatives generated through structure-based design. (D) The cyclic peptide-61 (CP61) amino acid sequence identified from screening a cyclic peptide library.