Genome-wide H3K27ac deposition in MCF-7 cells treated with p300 KAT inhibitor A-485
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ABSTRACT:
PROVIDER: PRJNA722293 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14247066_1.fastq.gz | Fastqsanger.gz | |||
| SRR14247066_2.fastq.gz | Fastqsanger.gz | |||
| SRR14247067_1.fastq.gz | Fastqsanger.gz | |||
| SRR14247067_2.fastq.gz | Fastqsanger.gz | |||
| SRR14247068_1.fastq.gz | Fastqsanger.gz |
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Project description:MCF-7 (Estrogen receptor positive breast cancer) cells were treated with p300 KAT inhibitor A-485 and genome wide H3K27ac deposition was measured by ChIP-seq.
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Project description:MCF-7 cells treated with p300 KAT inhibitor A-485
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Project description:SOX10 is a lineage-specific transcription factor critical for melanoma tumor growth, while SOX10 loss-of-function drives the emergence of therapy-resistant, invasive melanoma phenotypes. A major challenge has been developing therapeutic strategies targeting SOX10’s role in melanoma proliferation, while preventing a concomitant increase in tumor cell invasion. We found that the lysine acetyltransferase (KAT) EP300 and SOX10 gene loci on Chromosome 22 are frequently co-amplified in melanomas, including UV-associated and acral tumors. We further show that p300 KAT activity mediates SOX10 protein stability and that the p300 inhibitor, A-485, downregulates SOX10 protein levels in melanoma cells via proteasome-mediated degradation. Additionally, A-485 potently inhibits proliferation of SOX10+ melanoma cells while decreasing invasion in AXLhigh/MITFlow melanoma cells through downregulation of metastasis-related genes. We conclude that the SOX10/p300 axis is critical to melanoma growth and invasion, and that inhibition of p300 KAT activity through A-485 may be a worthwhile therapeutic approach for SOX10-reliant tumors.
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Project description:Expression data from MCF-7 cells treated with p300 KAT inhibitor A-485
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Project description:The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) was discovered more than 2 decades ago and the enzymatic function of these enzymes are established as a major epigenetic regulatory mechanism of gene transcription. Thus, these epigenetic modifiers are involved in multiple diseases and represent attractive targets for therapeutic intervention. While HDAC inhibitors have been developed and approved by the FDA to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (here called p300/CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products and bisubstrate analogs such as Lys-CoA either lack potency and selectivity or suffer from poor cellular permeability. C646 is widely utilized as a tool to inhibit p300/CBP HAT activity, but its off-target activity and reactivity may limit its cellular specificity. Here, we describe A-485 as a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a pharmacologically active small molecule (A-485) bound to the catalytic active site of p300 HAT domain and demonstrate that A-485 is an acetyl-CoA competitive inhibitor of p300/CBP. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 robustly inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively drugging the catalytic activity of histone acetyltransferases, provide the framework for delineating the enzymatic functions of HATs, and pave the way for the development of novel therapeutics targeting HAT activity.
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Project description:The oncogenic transcription factor (TF) IRF4 is a universal multiple myeloma (MM) dependency that remains undrugged owing to its disordered structure. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic approach to nominate druggable TF cofactors, we identified the chromatin coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. We developed KB528, a highly selective p300 KAT inhibitor to explore the regulatory relationship between IRF4 and p300. Instead of broadly inhibiting transcription, partial p300 KAT inhibition selectively downregulates IRF4 and its downstream gene expression program leading to apoptosis selectively in MM cells. IRF4 dependency is a hallmark of MM that exists downstream of existing MM therapies. Consequently, p300 KAT inhibition exhibits strong antiproliferative activity ex vivo and in vivo as a single agent as well as in combination regimens in treatment refractory models. p300 KAT inhibition is well-tolerated in vivo motivating further clinical development in MM.
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Project description:The oncogenic transcription factor (TF) IRF4 is a universal multiple myeloma (MM) dependency that remains undrugged owing to its disordered structure. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic approach to nominate druggable TF cofactors, we identified the chromatin coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. We developed KB528, a highly selective p300 KAT inhibitor to explore the regulatory relationship between IRF4 and p300. Instead of broadly inhibiting transcription, partial p300 KAT inhibition selectively downregulates IRF4 and its downstream gene expression program leading to apoptosis selectively in MM cells. IRF4 dependency is a hallmark of MM that exists downstream of existing MM therapies. Consequently, p300 KAT inhibition exhibits strong antiproliferative activity ex vivo and in vivo as a single agent as well as in combination regimens in treatment refractory models. p300 KAT inhibition is well-tolerated in vivo motivating further clinical development in MM.
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Project description:The oncogenic transcription factor (TF) IRF4 is a universal multiple myeloma (MM) dependency that remains undrugged owing to its disordered structure. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic approach to nominate druggable TF cofactors, we identified the chromatin coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. We developed KB528, a highly selective p300 KAT inhibitor to explore the regulatory relationship between IRF4 and p300. Instead of broadly inhibiting transcription, partial p300 KAT inhibition selectively downregulates IRF4 and its downstream gene expression program leading to apoptosis selectively in MM cells. IRF4 dependency is a hallmark of MM that exists downstream of existing MM therapies. Consequently, p300 KAT inhibition exhibits strong antiproliferative activity ex vivo and in vivo as a single agent as well as in combination regimens in treatment refractory models. p300 KAT inhibition is well-tolerated in vivo motivating further clinical development in MM.
2025-10-20 | GSE274593 | GEO
Project description:The oncogenic transcription factor (TF) IRF4 is a universal multiple myeloma (MM) dependency that remains undrugged owing to its disordered structure. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic approach to nominate druggable TF cofactors, we identified the chromatin coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. We developed KB528, a highly selective p300 KAT inhibitor to explore the regulatory relationship between IRF4 and p300. Instead of broadly inhibiting transcription, partial p300 KAT inhibition selectively downregulates IRF4 and its downstream gene expression program leading to apoptosis selectively in MM cells. IRF4 dependency is a hallmark of MM that exists downstream of existing MM therapies. Consequently, p300 KAT inhibition exhibits strong antiproliferative activity ex vivo and in vivo as a single agent as well as in combination regimens in treatment refractory models. p300 KAT inhibition is well-tolerated in vivo motivating further clinical development in MM.
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