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Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer

ABSTRACT: Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer

PROVIDER: PRJNA671678 | ENA |

REPOSITORIES: ENA

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Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer [ChIP-seq]

Project description:Tumor microenvironment promotes tumorigenesis, but its role in modulating tumor chromatin activity is poorly understood. Here, we show that inflammatory cytokines interleukin-6 and -8 in the tumor microenvironment induces JAK2-mediated phosphorylation of bromodomain-containing protein 4 (BRD4), which results in interaction with UCHL3 deubiquitinase, leading to increased BRD4 protein stabilization in colorectal cancer. JAK2-phosphorylated BRD4 shows enhanced activity binding to chromatin but reduced binding to BRD4 inhibitors, leading to treatment resistance. Moreover, BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Thus, the inflammatory tumor microenvironment provides a powerful mechanism for tumor chromatin remodeling and oncogenic transcription, which suggests a unrecognized new strategy to enhance BRD4 inhibitor response.

2021-06-07 | GSE160352 | GEO

Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer [ChIP-seq]

Project description:Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer [ChIP-seq]

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Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer

Project description:Analysis of gene expression profiles of patient-derived colorectal cancer cell which is mono-cultured or co-cultured with CAFs in the presence of vehicle, JQ1, pacritinib or combo.

2021-06-08 | GSE160035 | GEO

BRD4 connects enhancer remodeling to senescence immune surveillance

Project description:BRD4 connects enhancer remodeling to senescence immune surveillance

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BRD4 connects enhancer remodeling to senescence immune surveillance (ChIP-Seq)

Project description:Cellular senescence is a homeostatic program associated with tumor suppression, wound healing, and certain age related pathologies. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while at the same time activate an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell-mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.

2016-04-15 | GSE74238 | GEO

BRD4 connects enhancer remodeling to senescence immune surveillance (RNA-seq)

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Regulation of the KEAP1/NRF2 oxidative stress response pathway by BRD4 in prostate and colorectal cancer

Project description:To identify genes regulated by BRD4 and to provide insight into new mechanisms de-regulated by BRD4, such as the response to oxidative stress, we integrated BRD4-binding regions with BRD4 gene expression data. For this analysis we performed BRD4 chromatin immunoprecipitation experiments and BRD4 knock down experiments followed by RNA-Seq analyses. By integration of both gene lists we identified top candidate genes regulated by BRD4. HEK cells have been investigated for genomewide BRD4 binding sites and expression changes after knock down of BRD4. Illumina sequencing was used to gather data of the type ChIP Seq and mRNA Seq.

2014-02-28 | E-GEOD-50491 | biostudies-arrayexpress

QPCTL deletion results in a rewiring of the tumor microenvironment

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Determination of the tumor microenvironment remodeling by KRAS targeted therapy in pancreatic cancer

Project description:Determination of the tumor microenvironment remodeling by KRAS targeted therapy in pancreatic cancer

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Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer.

Project description:BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.

| S-EPMC8295257 | biostudies-literature

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