Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein
- Autores
- 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; Jones, Alana; Kabbout, Mohamed; Vohra, Nasreen; Nápoles, Anna María; Singhal, Sandeep; Yancey, Ryan; de Siervi, Adriana; Gardner, Kevin
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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.
Fil: Byun, Jung S.. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Park, Samson. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Yi, Dae Ik. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Shin, Jee Hye. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Hernandez, Sara Gil. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Hewitt, Stephen M.. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Nicklaus, Marc C.. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Peach, Megan L.. Leidos Biomedical Research ; Estados Unidos
Fil: Guasch, Laura. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Tang, Binwu. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Wakefield, Lalage M.. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Yan, Tingfen. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Caban, Ambar. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Jones, Alana. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Kabbout, Mohamed. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Vohra, Nasreen. East Carolina University; Estados Unidos
Fil: Nápoles, Anna María. Public Health Service. National Institute Of Health; Estados Unidos
Fil: Singhal, Sandeep. Columbia University; Estados Unidos
Fil: Yancey, Ryan. Columbia University; Estados Unidos
Fil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Gardner, Kevin. Public Health Service. National Institute Of Health; Estados Unidos. Columbia University; Estados Unidos - Materia
-
BREAST CANCER
TARGET VALIDATION - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/106315
Ver los metadatos del registro completo
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Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding proteinByun, Jung S.Park, SamsonYi, Dae IkShin, Jee HyeHernandez, Sara GilHewitt, Stephen M.Nicklaus, Marc C.Peach, Megan L.Guasch, LauraTang, BinwuWakefield, Lalage M.Yan, TingfenCaban, AmbarJones, AlanaKabbout, MohamedVohra, NasreenNápoles, Anna MaríaSinghal, SandeepYancey, Ryande Siervi, AdrianaGardner, KevinBREAST CANCERTARGET VALIDATIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The 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.Fil: Byun, Jung S.. Public Health Service. National Institute Of Health; Estados UnidosFil: Park, Samson. Public Health Service. National Institute Of Health; Estados UnidosFil: Yi, Dae Ik. Public Health Service. National Institute Of Health; Estados UnidosFil: Shin, Jee Hye. Public Health Service. National Institute Of Health; Estados UnidosFil: Hernandez, Sara Gil. Public Health Service. National Institute Of Health; Estados UnidosFil: Hewitt, Stephen M.. Public Health Service. National Institute Of Health; Estados UnidosFil: Nicklaus, Marc C.. Public Health Service. National Institute Of Health; Estados UnidosFil: Peach, Megan L.. Leidos Biomedical Research ; Estados UnidosFil: Guasch, Laura. Public Health Service. National Institute Of Health; Estados UnidosFil: Tang, Binwu. Public Health Service. National Institute Of Health; Estados UnidosFil: Wakefield, Lalage M.. Public Health Service. National Institute Of Health; Estados UnidosFil: Yan, Tingfen. Public Health Service. National Institute Of Health; Estados UnidosFil: Caban, Ambar. Public Health Service. National Institute Of Health; Estados UnidosFil: Jones, Alana. Public Health Service. National Institute Of Health; Estados UnidosFil: Kabbout, Mohamed. Public Health Service. National Institute Of Health; Estados UnidosFil: Vohra, Nasreen. East Carolina University; Estados UnidosFil: Nápoles, Anna María. Public Health Service. National Institute Of Health; Estados UnidosFil: Singhal, Sandeep. Columbia University; Estados UnidosFil: Yancey, Ryan. Columbia University; Estados UnidosFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gardner, Kevin. Public Health Service. National Institute Of Health; Estados Unidos. Columbia University; Estados UnidosNLM (Medline)2019-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/106315Byun, Jung S.; Park, Samson; Yi, Dae Ik; Shin, Jee Hye; Hernandez, Sara Gil; et al.; Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein; NLM (Medline); Cell death & disease; 10; 689; 9-20192041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41419-019-1892-7info:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-019-1892-7info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:00:20Zoai:ri.conicet.gov.ar:11336/106315instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:00:20.281CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| title |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| spellingShingle |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein Byun, Jung S. BREAST CANCER TARGET VALIDATION |
| title_short |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| title_full |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| title_fullStr |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| title_full_unstemmed |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| title_sort |
Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein |
| dc.creator.none.fl_str_mv |
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 Jones, Alana Kabbout, Mohamed Vohra, Nasreen Nápoles, Anna María Singhal, Sandeep Yancey, Ryan de Siervi, Adriana Gardner, Kevin |
| author |
Byun, Jung S. |
| author_facet |
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 Jones, Alana Kabbout, Mohamed Vohra, Nasreen Nápoles, Anna María Singhal, Sandeep Yancey, Ryan de Siervi, Adriana Gardner, Kevin |
| author_role |
author |
| author2 |
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 Jones, Alana Kabbout, Mohamed Vohra, Nasreen Nápoles, Anna María Singhal, Sandeep Yancey, Ryan de Siervi, Adriana Gardner, Kevin |
| author2_role |
author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
BREAST CANCER TARGET VALIDATION |
| topic |
BREAST CANCER TARGET VALIDATION |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
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. Fil: Byun, Jung S.. Public Health Service. National Institute Of Health; Estados Unidos Fil: Park, Samson. Public Health Service. National Institute Of Health; Estados Unidos Fil: Yi, Dae Ik. Public Health Service. National Institute Of Health; Estados Unidos Fil: Shin, Jee Hye. Public Health Service. National Institute Of Health; Estados Unidos Fil: Hernandez, Sara Gil. Public Health Service. National Institute Of Health; Estados Unidos Fil: Hewitt, Stephen M.. Public Health Service. National Institute Of Health; Estados Unidos Fil: Nicklaus, Marc C.. Public Health Service. National Institute Of Health; Estados Unidos Fil: Peach, Megan L.. Leidos Biomedical Research ; Estados Unidos Fil: Guasch, Laura. Public Health Service. National Institute Of Health; Estados Unidos Fil: Tang, Binwu. Public Health Service. National Institute Of Health; Estados Unidos Fil: Wakefield, Lalage M.. Public Health Service. National Institute Of Health; Estados Unidos Fil: Yan, Tingfen. Public Health Service. National Institute Of Health; Estados Unidos Fil: Caban, Ambar. Public Health Service. National Institute Of Health; Estados Unidos Fil: Jones, Alana. Public Health Service. National Institute Of Health; Estados Unidos Fil: Kabbout, Mohamed. Public Health Service. National Institute Of Health; Estados Unidos Fil: Vohra, Nasreen. East Carolina University; Estados Unidos Fil: Nápoles, Anna María. Public Health Service. National Institute Of Health; Estados Unidos Fil: Singhal, Sandeep. Columbia University; Estados Unidos Fil: Yancey, Ryan. Columbia University; Estados Unidos Fil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Gardner, Kevin. Public Health Service. National Institute Of Health; Estados Unidos. Columbia University; Estados Unidos |
| description |
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. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019-09 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/106315 Byun, Jung S.; Park, Samson; Yi, Dae Ik; Shin, Jee Hye; Hernandez, Sara Gil; et al.; Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein; NLM (Medline); Cell death & disease; 10; 689; 9-2019 2041-4889 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/106315 |
| identifier_str_mv |
Byun, Jung S.; Park, Samson; Yi, Dae Ik; Shin, Jee Hye; Hernandez, Sara Gil; et al.; Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein; NLM (Medline); Cell death & disease; 10; 689; 9-2019 2041-4889 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
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info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41419-019-1892-7 info:eu-repo/semantics/altIdentifier/doi/10.1038/s41419-019-1892-7 |
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openAccess |
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application/pdf application/pdf |
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NLM (Medline) |
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NLM (Medline) |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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