Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein.

Cell death & disease 2019 Sep 18

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The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.

Citation

Jung S Byun, Samson Park, Dae Ik Yi, Jee-Hye Shin, Sara Gil Hernandez, Stephen M Hewitt, Marc C Nicklaus, Megan L Peach, Laura Guasch, Binwu Tang, Lalage M Wakefield, Tingfen Yan, Ambar Caban, Alana Jones, Mohamed Kabbout, Nasreen Vohra, Anna María Nápoles, Sandeep Singhal, Ryan Yancey, Adriana De Siervi, Kevin Gardner. Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein. Cell death & disease. 2019 Sep 18;10(10):689