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

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

PROVIDER: PRJNA672986 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12926830_1.fastq.gz	Fastqsanger.gz
	SRR12926830_2.fastq.gz	Fastqsanger.gz
	SRR12926831_1.fastq.gz	Fastqsanger.gz
	SRR12926831_2.fastq.gz	Fastqsanger.gz
	SRR12926832_1.fastq.gz	Fastqsanger.gz

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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.

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

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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.

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