CREBBP/EP300 acetyltransferase inhibition targets lineage specific enhancers to inhibit the proliferation of ER+ breast cancer cells [scATAC-Seq]
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ABSTRACT:
PROVIDER: PRJNA786008 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:MCF7 cells were treated with a CREBBP/EP300 acetyltransferase inhibitor CPI-1612 and chromatin status was measured via single-cell ATAC-seq
2022-03-04 | GSE190162 | GEO
Project description:MCF7 cells were treated with a CREBBP/EP300 acetyltransferase inhibitor CPI-1612 and chromatin status was measured via ATAC-seq
2022-03-04 | GSE190159 | GEO
Project description:MCF7 were treated with a CREBBP/EP300 acetyltransferase inhibitor CPI-1612 or DMSO and ChIP-seq was performed for H3K27ac and H3K9ac.
2022-03-04 | GSE190161 | GEO
Project description:MCF7, T47D, or ZR751 cells were treated with a CREBBP/EP300 acetyltransferase inhibitor CPI-1612 and/or Fulvestrant and expression changes were measured via RNA-seq
2022-03-04 | GSE190160 | GEO
Project description:The androgen receptor (AR) serves as the primary target for therapeutic intervention in prostate cancer (PCa), and AR-targeted treatments constitute the cornerstone of clinical management for this malignancy. Nevertheless, their effectiveness is often compromised by the emergence of resistance mechanisms. These resistant forms of PCa persist in activating AR signaling, highlighting the urgent need for new therapeutic strategies to combat therapy-resistant PCa. Resistance to AR-targeted therapies can manifest through a multitude of mechanisms, including the overexpression of AR splice variants and altered activities of other transcription factors, such as the glucocorticoid receptor (GR) and FOXA1. A shared characteristic among these transcription factors is their dependence on a common set of coregulators, with EP300/CREBBP being a prominent example. This suggests a compelling rationale for employing coregulatory-targeted therapies in the management of treatment-resistant PCa. Here, we aimed to explore the impact of EP300/CREBBP acetyltransferase inhibition on steroid receptor and FOXA1 signaling in PCa cells, employing genome-wide techniques. Our findings illuminate that EP300/CREBBP inhibition exerts a substantial disruptive effect on the AR-regulated transcriptome and receptor chromatin binding, primarily by downregulating the AR-gene. Similarly, the transcriptome regulated by GR and the chromatin binding of the receptor were also hindered, although this was not associated with decreased GR expression levels. Instead, EP300/CREBBP acetyltransferase inhibition leads to a significant reduction in FOXA1 chromatin binding, consequently constraining GR signaling. In summary, our results emphasize how EP300/CREBBP acetyltransferase inhibition distinctly curtails the signaling activities of oncogenic transcription factors, underscoring the potential effectiveness of coregulatory-targeted therapies in PCa.
2024-03-14 | GSE245968 | GEO
Project description:The androgen receptor (AR) serves as the primary target for therapeutic intervention in prostate cancer (PCa), and AR-targeted treatments constitute the cornerstone of clinical management for this malignancy. Nevertheless, their effectiveness is often compromised by the emergence of resistance mechanisms. These resistant forms of PCa persist in activating AR signaling, highlighting the urgent need for new therapeutic strategies to combat therapy-resistant PCa. Resistance to AR-targeted therapies can manifest through a multitude of mechanisms, including the overexpression of AR splice variants and altered activities of other transcription factors, such as the glucocorticoid receptor (GR) and FOXA1. A shared characteristic among these transcription factors is their dependence on a common set of coregulators, with EP300/CREBBP being a prominent example. This suggests a compelling rationale for employing coregulatory-targeted therapies in the management of treatment-resistant PCa. Here, we aimed to explore the impact of EP300/CREBBP acetyltransferase inhibition on steroid receptor and FOXA1 signaling in PCa cells, employing genome-wide techniques. Our findings illuminate that EP300/CREBBP inhibition exerts a substantial disruptive effect on the AR-regulated transcriptome and receptor chromatin binding, primarily by downregulating the AR-gene. Similarly, the transcriptome regulated by GR and the chromatin binding of the receptor were also hindered, although this was not associated with decreased GR expression levels. Instead, EP300/CREBBP acetyltransferase inhibition leads to a significant reduction in FOXA1 chromatin binding, consequently constraining GR signaling. In summary, our results emphasize how EP300/CREBBP acetyltransferase inhibition distinctly curtails the signaling activities of oncogenic transcription factors, underscoring the potential effectiveness of coregulatory-targeted therapies in PCa.
2024-03-14 | GSE245967 | GEO
Project description:The androgen receptor (AR) serves as the primary target for therapeutic intervention in prostate cancer (PCa), and AR-targeted treatments constitute the cornerstone of clinical management for this malignancy. Nevertheless, their effectiveness is often compromised by the emergence of resistance mechanisms. These resistant forms of PCa persist in activating AR signaling, highlighting the urgent need for new therapeutic strategies to combat therapy-resistant PCa. Resistance to AR-targeted therapies can manifest through a multitude of mechanisms, including the overexpression of AR splice variants and altered activities of other transcription factors, such as the glucocorticoid receptor (GR) and FOXA1. A shared characteristic among these transcription factors is their dependence on a common set of coregulators, with EP300/CREBBP being a prominent example. This suggests a compelling rationale for employing coregulatory-targeted therapies in the management of treatment-resistant PCa. Here, we aimed to explore the impact of EP300/CREBBP acetyltransferase inhibition on steroid receptor and FOXA1 signaling in PCa cells, employing genome-wide techniques. Our findings illuminate that EP300/CREBBP inhibition exerts a substantial disruptive effect on the AR-regulated transcriptome and receptor chromatin binding, primarily by downregulating the AR-gene. Similarly, the transcriptome regulated by GR and the chromatin binding of the receptor were also hindered, although this was not associated with decreased GR expression levels. Instead, EP300/CREBBP acetyltransferase inhibition leads to a significant reduction in FOXA1 chromatin binding, consequently constraining GR signaling. In summary, our results emphasize how EP300/CREBBP acetyltransferase inhibition distinctly curtails the signaling activities of oncogenic transcription factors, underscoring the potential effectiveness of coregulatory-targeted therapies in PCa.
2024-03-14 | GSE245966 | GEO
Project description:Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.
2020-02-19 | GSE132365 | GEO
Project description:Somatic mutations affecting CREBBP and EP300 are a hallmark of Diffuse Large B Cell Lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small molecule inhibitors of CARM1 in DLBCL and other cancers.
2020-06-18 | GSE152666 | GEO
Project description:Somatic mutations affecting CREBBP and EP300 are a hallmark of Diffuse Large B Cell Lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small molecule inhibitors of CARM1 in DLBCL and other cancers.
2020-06-18 | GSE152665 | GEO