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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE152668 | GEO | 2020/06/18

REPOSITORIES: GEO

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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas.

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.

| S-EPMC7688486 | biostudies-literature

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

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 | GSE152667 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

2020-06-18 | GSE152666 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

2020-06-18 | GSE152665 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas

| PRJNA640005 | ENA

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

| PRJNA640009 | ENA

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

| PRJNA640008 | ENA

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

| PRJNA640010 | ENA

EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells.

Project description:The androgen receptor (AR) is a primary target for treating prostate cancer (PCa), forming the bedrock of its clinical management. Despite their efficacy, resistance often hampers AR-targeted therapies, necessitating new strategies against therapy-resistant PCa. These resistances involve various mechanisms, including AR splice variant overexpression and altered activities of transcription factors like the glucocorticoid receptor (GR) and FOXA1. These factors rely on common coregulators, such as EP300/CREBBP, suggesting a rationale for coregulator-targeted therapies. Our study explores EP300/CREBBP acetyltransferase inhibition's impact on steroid receptor and FOXA1 signaling in PCa cells using genome-wide techniques. Results reveal that EP300/CREBBP inhibition significantly disrupts the AR-regulated transcriptome and receptor chromatin binding by reducing the AR-gene expression. Similarly, GR's regulated transcriptome and receptor binding were hindered, not linked to reduced GR expression but to diminished FOXA1 chromatin binding, restricting GR signaling. Overall, our findings highlight how EP300/CREBBP inhibition distinctively curtails oncogenic transcription factors' signaling, suggesting the potential of coregulatory-targeted therapies in PCa.

| S-EPMC10987371 | biostudies-literature

Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function.

Project description:Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.

| S-EPMC8566594 | biostudies-literature

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