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A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells

A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells
A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells
Identification of direct modulators of transcription factor protein–protein interactions is a key challenge for ligand discovery that promises to significantly advance current approaches to cancer therapy. Here, we report an inhibitor of NADH-dependent dimerization of the C-terminal binding protein (CtBP) transcriptional repressor, identified by screening genetically encoded cyclic peptide libraries of up to 64 million members. CtBP dimers form the core of transcription complexes associated with epigenetic regulation of multiple genes that control many characteristics of cancer cells, including proliferation, survival and migration. CtBP monomers also have distinct and critical cellular function, thus current experimental tools that deplete all forms of a targeted protein (e.g. siRNA) do not allow the cellular consequences of this metabolically regulated transcription factor to be deciphered. The most potent inhibitor from our screen (cyclo-SGWTVVRMY) is demonstrated to disrupt CtBP dimerization in vitro and in cells. This compound is used as a chemical tool to establish that the NADH-dependent dimerization of CtBPs regulates the maintenance of mitotic fidelity in cancer cells. Treatment of highly glycolytic breast cancer cell lines with the identified inhibitor significantly reduced their mitotic fidelity, proliferation and colony forming potential, whereas the compound does not affect mitotic fidelity of cells with lower glycolytic flux. This work not only links the altered metabolic state of transformed cells to a key determinant of the tumor cell phenotype, but the uncovered compound also serves as the starting point for the development of potential therapeutic agents that target tumors by disrupting the CtBP chromatin-modifying complex.
1478-6524
3046-3057
Birts, Charles N.
8689ddad-ba47-4ca6-82c5-001315dbd250
Nijjar, Sharandip K.
ec7a6e38-42b1-4177-aa41-2884150ea97c
Mardle, Charlotte A.
a85cbf7c-10b3-4c41-acc3-94f98ef5c0c5
Hoakwie, Franciane
be6ab35d-4511-45ae-b059-32ae7b4236af
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Birts, Charles N.
8689ddad-ba47-4ca6-82c5-001315dbd250
Nijjar, Sharandip K.
ec7a6e38-42b1-4177-aa41-2884150ea97c
Mardle, Charlotte A.
a85cbf7c-10b3-4c41-acc3-94f98ef5c0c5
Hoakwie, Franciane
be6ab35d-4511-45ae-b059-32ae7b4236af
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Birts, Charles N., Nijjar, Sharandip K., Mardle, Charlotte A., Hoakwie, Franciane, Duriez, Patrick J., Blaydes, Jeremy P. and Tavassoli, Ali (2013) A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells. Chemical Science, 4 (8), 3046-3057. (doi:10.1039/c3sc50481f).

Record type: Article

Abstract

Identification of direct modulators of transcription factor protein–protein interactions is a key challenge for ligand discovery that promises to significantly advance current approaches to cancer therapy. Here, we report an inhibitor of NADH-dependent dimerization of the C-terminal binding protein (CtBP) transcriptional repressor, identified by screening genetically encoded cyclic peptide libraries of up to 64 million members. CtBP dimers form the core of transcription complexes associated with epigenetic regulation of multiple genes that control many characteristics of cancer cells, including proliferation, survival and migration. CtBP monomers also have distinct and critical cellular function, thus current experimental tools that deplete all forms of a targeted protein (e.g. siRNA) do not allow the cellular consequences of this metabolically regulated transcription factor to be deciphered. The most potent inhibitor from our screen (cyclo-SGWTVVRMY) is demonstrated to disrupt CtBP dimerization in vitro and in cells. This compound is used as a chemical tool to establish that the NADH-dependent dimerization of CtBPs regulates the maintenance of mitotic fidelity in cancer cells. Treatment of highly glycolytic breast cancer cell lines with the identified inhibitor significantly reduced their mitotic fidelity, proliferation and colony forming potential, whereas the compound does not affect mitotic fidelity of cells with lower glycolytic flux. This work not only links the altered metabolic state of transformed cells to a key determinant of the tumor cell phenotype, but the uncovered compound also serves as the starting point for the development of potential therapeutic agents that target tumors by disrupting the CtBP chromatin-modifying complex.

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Published date: 14 June 2013
Organisations: Molecular Diagnostics & Thereputics

Identifiers

Local EPrints ID: 353748
URI: https://eprints.soton.ac.uk/id/eprint/353748
ISSN: 1478-6524
PURE UUID: 5faa633d-613c-447e-a695-7c32e98b4e52
ORCID for Charles N. Birts: ORCID iD orcid.org/0000-0002-0368-8766
ORCID for Jeremy P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 17 Jun 2013 10:52
Last modified: 20 Jul 2019 01:06

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