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CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation

BACKGROUND: The reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. RESULTS: We report that the bromodomai...

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Autores principales: Garcia-Carpizo, Veronica, Ruiz-Llorente, Sergio, Sarmentero, Jacinto, Graña-Castro, Osvaldo, Pisano, David G., Barrero, Maria J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992658/
https://www.ncbi.nlm.nih.gov/pubmed/29884215
http://dx.doi.org/10.1186/s13072-018-0197-x
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author Garcia-Carpizo, Veronica
Ruiz-Llorente, Sergio
Sarmentero, Jacinto
Graña-Castro, Osvaldo
Pisano, David G.
Barrero, Maria J.
author_facet Garcia-Carpizo, Veronica
Ruiz-Llorente, Sergio
Sarmentero, Jacinto
Graña-Castro, Osvaldo
Pisano, David G.
Barrero, Maria J.
author_sort Garcia-Carpizo, Veronica
collection PubMed
description BACKGROUND: The reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. RESULTS: We report that the bromodomains of the histone acetyltransferases CREBBP/EP300 are critical to sustain the proliferation of human leukemia and lymphoma cell lines. EP300 is very abundant at super-enhancers in K562 and is coincident with sites of GATA1 and MYC occupancy. In accordance, CREBBP/EP300 bromodomain inhibitors interfere with GATA1- and MYC-driven transcription, causing the accumulation of cells in the G0/G1 phase of the cell cycle. The CREBBP/CBP30 bromodomain inhibitor CBP30 displaces CREBBP and EP300 from GATA1 and MYC binding sites at enhancers, resulting in a decrease in the levels of histone acetylation at these regulatory regions and consequently reduced gene expression of critical genes controlled by these transcription factors. CONCLUSIONS: Our data shows that inhibition of CREBBP/EP300 bromodomains can interfere with oncogene-driven transcriptional programs in cancer cells and consequently hold therapeutic potential. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13072-018-0197-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-59926582018-06-21 CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation Garcia-Carpizo, Veronica Ruiz-Llorente, Sergio Sarmentero, Jacinto Graña-Castro, Osvaldo Pisano, David G. Barrero, Maria J. Epigenetics Chromatin Research BACKGROUND: The reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. RESULTS: We report that the bromodomains of the histone acetyltransferases CREBBP/EP300 are critical to sustain the proliferation of human leukemia and lymphoma cell lines. EP300 is very abundant at super-enhancers in K562 and is coincident with sites of GATA1 and MYC occupancy. In accordance, CREBBP/EP300 bromodomain inhibitors interfere with GATA1- and MYC-driven transcription, causing the accumulation of cells in the G0/G1 phase of the cell cycle. The CREBBP/CBP30 bromodomain inhibitor CBP30 displaces CREBBP and EP300 from GATA1 and MYC binding sites at enhancers, resulting in a decrease in the levels of histone acetylation at these regulatory regions and consequently reduced gene expression of critical genes controlled by these transcription factors. CONCLUSIONS: Our data shows that inhibition of CREBBP/EP300 bromodomains can interfere with oncogene-driven transcriptional programs in cancer cells and consequently hold therapeutic potential. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13072-018-0197-x) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-08 /pmc/articles/PMC5992658/ /pubmed/29884215 http://dx.doi.org/10.1186/s13072-018-0197-x Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Garcia-Carpizo, Veronica
Ruiz-Llorente, Sergio
Sarmentero, Jacinto
Graña-Castro, Osvaldo
Pisano, David G.
Barrero, Maria J.
CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
title CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
title_full CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
title_fullStr CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
title_full_unstemmed CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
title_short CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation
title_sort crebbp/ep300 bromodomains are critical to sustain the gata1/myc regulatory axis in proliferation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992658/
https://www.ncbi.nlm.nih.gov/pubmed/29884215
http://dx.doi.org/10.1186/s13072-018-0197-x
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