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

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

Content Provider	Royal Society of Chemistry (RSC)
Author	Duriez, Patrick J. Blaydes, Jeremy P. Mardle, Charlotte A. Birts, Charles N. Hoakwie, Franciane Tavassoli, Ali Nijjar, Sharandip K.
Copyright Year	2013
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.
Starting Page	3046
Ending Page	3057
Page Count	12
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	4
Issue Number	8
Journal	Chemical Science
DOI	10.1039/c3sc50481f
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Ligand Determinant Enzyme inhibitor Small interfering RNA Ant colony Breast cancer C-terminus Protein Cyclic peptide Phenotype Epigenetics Transcription factor Cancer
Content Type	Text
Resource Type	Article
Subject	Chemistry

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Down-regulation of cx43 by retroviral delivery of small interfering rna promotes an aggressive breast cancer cell phenotype (2005).

C-terminal binding proteins play a critical nuclear function in the mitotic fidelity of breast cancer cells

Poly(A) binding protein (PABP) homeostasis is mediated by the stability of its inhibitor, Paip2.

Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development.

C-terminal binding proteins play a critical nuclear function in the mitotic fidelity of breast cancer cells

Mammalian hsp70 and hsp110.

A novel role for C-terminal binding proteins in the regulation of mitotic fidelity in breast cancer cells

Dimerization of the testis brain RNA-binding protein (translin) is mediated through its C-terminus and is required for DNA- and RNA-binding.

Isoliquiritigenin attenuates MiR-21 expression via induction of PIAS3 in breast cancer cells

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

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Down-regulation of cx43 by retroviral delivery of small interfering rna promotes an aggressive breast cancer cell phenotype (2005).

C-terminal binding proteins play a critical nuclear function in the mitotic fidelity of breast cancer cells

Poly(A) binding protein (PABP) homeostasis is mediated by the stability of its inhibitor, Paip2.

Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development.

C-terminal binding proteins play a critical nuclear function in the mitotic fidelity of breast cancer cells

Mammalian hsp70 and hsp110.

A novel role for C-terminal binding proteins in the regulation of mitotic fidelity in breast cancer cells

Dimerization of the testis brain RNA-binding protein (translin) is mediated through its C-terminus and is required for DNA- and RNA-binding.

Isoliquiritigenin attenuates MiR-21 expression via induction of PIAS3 in breast cancer cells

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