CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells.
Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alt...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0262378 |
| _version_ | 1818201149274062848 |
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| author | Archana Bommi-Reddy Sungmi Park-Chouinard David N Mayhew Esteban Terzo Aparna Hingway Michael J Steinbaugh Jonathan E Wilson Robert J Sims Andrew R Conery |
| author_facet | Archana Bommi-Reddy Sungmi Park-Chouinard David N Mayhew Esteban Terzo Aparna Hingway Michael J Steinbaugh Jonathan E Wilson Robert J Sims Andrew R Conery |
| author_sort | Archana Bommi-Reddy |
| collection | DOAJ |
| description | Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer. |
| first_indexed | 2024-12-12T02:48:58Z |
| format | Article |
| id | doaj.art-910a16c22594471fa25f0c86a1e97743 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T02:48:58Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-910a16c22594471fa25f0c86a1e977432022-12-22T00:40:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-01173e026237810.1371/journal.pone.0262378CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells.Archana Bommi-ReddySungmi Park-ChouinardDavid N MayhewEsteban TerzoAparna HingwayMichael J SteinbaughJonathan E WilsonRobert J SimsAndrew R ConeryTherapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.https://doi.org/10.1371/journal.pone.0262378 |
| spellingShingle | Archana Bommi-Reddy Sungmi Park-Chouinard David N Mayhew Esteban Terzo Aparna Hingway Michael J Steinbaugh Jonathan E Wilson Robert J Sims Andrew R Conery CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells. PLoS ONE |
| title | CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells. |
| title_full | CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells. |
| title_fullStr | CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells. |
| title_full_unstemmed | CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells. |
| title_short | CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells. |
| title_sort | crebbp ep300 acetyltransferase inhibition disrupts foxa1 bound enhancers to inhibit the proliferation of er breast cancer cells |
| url | https://doi.org/10.1371/journal.pone.0262378 |
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