Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein
Author
Byun, Jung S.; Park, Samson; Yi, Dae Ik; Shin, Jee-Hye; Hernandez, Sara Gil; Hewitt, Stephen M.; Nicklaus, Marc C.; Peach, Megan L.; Guasch, Laura; Tang, Binwu; Wakefield, Lalage M.; Yan, Tingfen; Caban, Ambar; Alana, Jones; Kabbout, Mohamed; Vohra, Nasreen; Nápoles, Anna María; Singhal, Sandeep; Yancey, Ryan; Siervi, Adriana De; Gardner, Kevin
Abstract
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.
Date
2019-08-08
Citation:
APA:
Byun, Jung S., & Park, Samson, & Yi, Dae Ik, & Shin, Jee-Hye, & Hernandez, Sara Gil, & Hewitt, Stephen M., & Nicklaus, Marc C., & Peach, Megan L., & Guasch, Laura, & Tang, Binwu, & Wakefield, Lalage M., & Yan, Tingfen, & Caban, Ambar, & Alana, Jones, & Kabbout, Mohamed, & Vohra, Nasreen, & Nápoles, Anna María, & Singhal, Sandeep, & Yancey, Ryan, & Siervi, Adriana De, & Gardner, Kevin. (August 2019).
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein.
,
(),
-
. Retrieved from
http://hdl.handle.net/10342/8073
MLA:
Byun, Jung S., and Park, Samson, and Yi, Dae Ik, and Shin, Jee-Hye, and Hernandez, Sara Gil, and Hewitt, Stephen M., and Nicklaus, Marc C., and Peach, Megan L., and Guasch, Laura, and Tang, Binwu, and Wakefield, Lalage M., and Yan, Tingfen, and Caban, Ambar, and Alana, Jones, and Kabbout, Mohamed, and Vohra, Nasreen, and Nápoles, Anna María, and Singhal, Sandeep, and Yancey, Ryan, and Siervi, Adriana De, and Gardner, Kevin.
"Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein". .
. (),
August 2019.
May 29, 2023.
http://hdl.handle.net/10342/8073.
Chicago:
Byun, Jung S. and Park, Samson and Yi, Dae Ik and Shin, Jee-Hye and Hernandez, Sara Gil and Hewitt, Stephen M. and Nicklaus, Marc C. and Peach, Megan L. and Guasch, Laura and Tang, Binwu and Wakefield, Lalage M. and Yan, Tingfen and Caban, Ambar and Alana, Jones and Kabbout, Mohamed and Vohra, Nasreen and Nápoles, Anna María and Singhal, Sandeep and Yancey, Ryan and Siervi, Adriana De and Gardner, Kevin,
"Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein," , no.
(August 2019),
http://hdl.handle.net/10342/8073 (accessed
May 29, 2023).
AMA:
Byun, Jung S., Park, Samson, Yi, Dae Ik, Shin, Jee-Hye, Hernandez, Sara Gil, Hewitt, Stephen M., Nicklaus, Marc C., Peach, Megan L., Guasch, Laura, Tang, Binwu, Wakefield, Lalage M., Yan, Tingfen, Caban, Ambar, Alana, Jones, Kabbout, Mohamed, Vohra, Nasreen, Nápoles, Anna María, Singhal, Sandeep, Yancey, Ryan, Siervi, Adriana De, Gardner, Kevin.
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein. .
August 2019;
():
.
http://hdl.handle.net/10342/8073. Accessed
May 29, 2023.
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