Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer

Li-Jun Di, Jung S. Byun, Madeline M. Wong, Clay Wakano, Tara Taylor, Sven Bilke, Songjoon Baek, Kent Hunter, Howard Yang, Maxwell Lee, Cecilia Zvosec, Galina Khramtsova, Fan Cheng, Charles M. Perou, C. Ryan Miller, Rachel Raab, Olufunmilayo I. Olopade and Kevin Gardner ()
Additional contact information
Li-Jun Di: Genetics Branch, National Cancer Institute
Jung S. Byun: Genetics Branch, National Cancer Institute
Madeline M. Wong: Genetics Branch, National Cancer Institute
Clay Wakano: Genetics Branch, National Cancer Institute
Tara Taylor: Genetics Branch, National Cancer Institute
Sven Bilke: Genetics Branch, National Cancer Institute
Songjoon Baek: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute
Kent Hunter: Laboratory of Cancer Biology and Genetics, National Cancer Institute
Howard Yang: Laboratory of Population Genetics, National Cancer Institute
Maxwell Lee: Laboratory of Population Genetics, National Cancer Institute
Cecilia Zvosec: University of Chicago
Galina Khramtsova: University of Chicago
Fan Cheng: Lineberger Comprehensive Cancer Care Center, University of North Carolina
Charles M. Perou: Lineberger Comprehensive Cancer Care Center, University of North Carolina
C. Ryan Miller: Lineberger Comprehensive Cancer Care Center, University of North Carolina
Rachel Raab: Leo W. Jenkins Cancer Center, East Carolina University
Olufunmilayo I. Olopade: University of Chicago
Kevin Gardner: Genetics Branch, National Cancer Institute

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively downregulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumours predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer.

Date: 2013
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DOI: 10.1038/ncomms2438

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