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The CTCF/LncRNA-PACERR/EP300 complex in TAMs promotes the malignant progression of pancreatic ductal adenocarcinoma (PDAC) by docking at the PTGS2 promoter region

ABSTRACT: The unregulated expression of COX-2 in tams is causally related to the occurrence, development and outcome of pancreatic ductal adenocarcinoma. We describe a new basic level of transcriptional control of COX-2 expression. Constructing in vivo and in vitro TAM model lines, we found that CTCF plays a significant role in the chromatin remodeling of pancreatic cancer-related macrophages, and showed that CTCF, which acts as both a transcription factor and an insulator, establishes an open chromatin domain, and Induced the expression of LncRNA PACERR in the upstream promoter region of PTGS2. The newly transcribed LncRNA PACERR binds to the RNA binding region of CTCF to play a cis-regulatory role. The formation of CTCF/LncRNA PACERR complex contributes to the recruitment of EP300 histone acetylation transfer, which increases the global scope of histone acetylation and induces the expression of PTGS2. Our findings reveal that CTCF and LncRNA that was regulated by CTCF at the same position work together to form a complex of CTCF/LncRNA PACERR/EP300 and dock in the PTGS2 promoter region to mediate the unexpected mechanism of PTGS2 expression. And LncRNA PACERR as a new potential target for regulating the malignant progression of pancreatic cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169451 | GEO | 2021/06/30

REPOSITORIES: GEO

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The CTCF/LncRNA-PACERR/EP300 complex in TAMs promotes the malignant progression of pancreatic ductal adenocarcinoma (PDAC) by docking at the PTGS2 promoter region

Project description:The CTCF/LncRNA-PACERR/EP300 complex in TAMs promotes the malignant progression of pancreatic ductal adenocarcinoma (PDAC) by docking at the PTGS2 promoter region

| PRJNA716651 | ENA

RNA-seq of lung myeloid cells from WT and Ptgs2-cKO mice

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2022-07-19 | E-MTAB-11888 | biostudies-arrayexpress

Single-cell transcriptional profiles of lung CD45+ immune cells from WT and Ptgs2-cKO mice

Project description:To better understand the role of the COX-2-dependent lung fibroblast program in modulating the lung immune microenvironment, we generated fibroblast-targeted Ptgs2 conditional knockout (cKO) mice by crossing Pdgfra-Cre mice with Ptgs2flox/flox mice. Then we determined how Ptgs2 deficiency in CD140a+ fibroblasts alters the lung immune microenvironment by performing single-cell RNA sequencing on lung CD45+ immune cells from WT and Ptgs2-cKO mice.

2022-07-19 | GSE206449 | GEO

Differential gene expression analysis of PTGS2-inducing and PTGS2-non-inducing oropharyngeal carcinoma cell lines.

Project description:Prostaglandin E2 (PGE2) is a powerful immunomodulator synthesized by the COX2 enzyme, coded by human gene PTGS2. PGE2 is known to possess angiogenic, protumor and immunosuppressive functionality in the microenviornment of oropharyngeal carcinomas (OPC). Differential induction of PTGS2 in infiltrating myeloid-derived immunocytes has been observed with media conditioned by cultured OPC biopsies and OPC-derived cell lines alike. To identify PTGS2-inducing, OPC-derived gene products, we utilized bluk RNA sequencing on 4 OPC-derived cell lines to compare expression profiles of PTGS2-inducing (SCC154, SCC25) with that of PTGS2-non-inducing (2A3, SCC152) cell lines. Interleukin-1α (IL-1α) was among the differentially expressed candidates between cell lines.

2022-10-21 | GSE215973 | GEO

EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer

Project description:Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5, also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis.

2023-10-24 | PXD039998 | Pride

Augmented Pla2g4c/Ptgs2/Hpgds Axis in Bronchial Tissues of Experimental Asthma

Project description:Rationale: Augmented smooth muscle contractility of the airways is one of the causes of airway hyperresponsiveness in asthmatics. However, the mechanism of the altered properties of airway smooth muscle cells is not well understood. Objectives: To identify differentially expressed genes (DEGs) related to the bronchial smooth muscle (BSM) hyper-contractility in a murine asthma model. Methods: The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Transcriptomic profiles were generated by microarray analysis of BSMs from the OA-challenged and control animals, and KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway Analysis was applied. Measurements and Main Results: Tension study showed a BSM hyperresponsiveness to acetylcholine (ACh) in the OA-challenged mice. A total of 770 genes were differentially expressed between the OA-challenged and control animals. Pathway analysis showed a significant change in arachidonic acid (AA) metabolism pathway in BSMs of the OA-challenged mice. Validation of DEGs by quantitative RT-PCR showed a significant increase in PLA2 group 4c (Pla2g4c)/COX-2 (Ptgs2)/PGD2 synthase 2 (Hpgds) axis. PGD2 level in bronchoalveolar fluids of the OA-challenged mice was significantly increased. A 24-h incubation of BSMs with PGD2 caused a hyperresponsiveness to ACh in naive control mice. Conclusions: AA metabolism is shifted towards PGD2 production in BSMs of asthma. Increased PGD2 level in the airways might be a cause of the BSM hyperresponsiveness in asthma.

2018-07-03 | GSE116504 | GEO

Pam3 generates immunosupressive macrophages using p38, MAPK and PTGS2 signaling

Project description:The gene expression pattern of PAM3 treated monocytes was compared to that of M-CSF, the conventional method of generating immunosuppressive macrophage. Pathways regulated by NF-KB and Akt played a central role in the general process of monocyte to macrophage differentiation. p38 MAPK and PTGS2 signaling biased this process towards the generation of immunosuppressive rather than pro-inflammatory macrophage whereas ERK and JNK were essential for Pam3 but not M-CSF driven maturation

2017-06-03 | GSE99609 | GEO

COX-2/PGE2 upregulation contributes to the chromosome 17p-deleted lymphoma

Project description:Chromosome 17p deletions are one of the most frequent chromosomal alterations in human cancers and also lymphoma. Although it has been assumed to be equal to p53 loss for a long time, there are emerging evidence suggesting that there would be additional p53–independent mechanisms. Our previous work identified ALOX15B, an arachidonate lipoxygenase, as a 17p tumor suppressor in lymphoma. Interestingly, five of the six ALOX genes locate on this region and frequently co-deleted with TP53. Among them, ALOX15B, ALOX12B and ALOXE3 are adjacent to one another and proximal to the centromere relative to TP53, while ALOX12 and ALOX15 are distal to the centromere relative to TP53. Herein, we show that each of the five 17p ALOX genes repress Myc-driven lymphomagenesis in mice. Mechanistically, deficiency of the ALOX arachidonate metabolism pathway activates the paralleling COX-PGE2 pathway, resulting in increasing PTGS2 expression and PGE2 level. PGE2 prevents apoptosis of pre-B cells and Ptgs2 knockdown extends the latency of Myc;shAlox15b lymphoma in vivo. Further, shAlox15b lymphoma cells are more sensitive to COX-2 inhibitor celecoxib than control lymphoma cells. Importantly, the ALOX-COX metabolism unbalance is also observed in human cancers with del(17p). Taken together, our studies reveal the tumor suppression functions of all of the five ALOX genes on chromosome 17p in lymphoma and an unprecedented arachidonate metabolism unbalance between the ALOX and COX pathways underlying human cancers with 17p deletions.

2022-12-21 | GSE147264 | GEO

Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression

Project description:We tested the hypothesis that increasing matrix stiffness on which normal human lung fibroblasts are grown promotes the expression of a fibrogenic cellular transcriptomic program. Keywords: Human lung fibroblast, matrix stiffness, PTGS2, COX-2, Prostaglandin E2

2010-07-15 | GSE22011 | GEO

EP300 selectively controls the enhancer landscape of MYCN-amplified neuroblastoma [RNA-seq xenograft]

Project description:Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastomas (NB) depend on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2?, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound termed ?JQAD1? that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP compensates. Comparing HAT inhibition and EP300-specific degradation, we identified a non-catalytic role for EP300 in promoting MYCN expression and repression of apoptosis.

2021-11-09 | GSE159616 | GEO

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