Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA240995 | ENA |
REPOSITORIES: ENA
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Project description:Recent studies including next-generation sequencing have identified genomic events in prostate cancer including ETS gene fusions. However, it is critical to identify druggable targets for prostate cancer and their mechanism of action for therapeutic intervention. Here, we show that prolyl 4-hydroxylase, alpha polypeptide I (P4HA1) is overexpressed in aggressive prostate cancer and amplified in a subset of metastatic prostate cancer. This study provides mechanistic insights of P4HA1 regulation and its mode of action including its role in regulating MMP1. Importantly, P4HA1 mediated invasion in cancer cells could be reversed using MMP1 inhibitor, revealing therapeutic utility of targeting P4HA1 either directly or by inhibiting its downstream effectors. Two-color experiment, in duplicates.
2015-05-10 | E-GEOD-55787 | biostudies-arrayexpress
Project description:Recent studies including next-generation sequencing have identified genomic events in prostate cancer including ETS gene fusions. However, it is critical to identify druggable targets for prostate cancer and their mechanism of action for therapeutic intervention. Here, we show that prolyl 4-hydroxylase, alpha polypeptide I (P4HA1) is overexpressed in aggressive prostate cancer and amplified in a subset of metastatic prostate cancer. This study provides mechanistic insights of P4HA1 regulation and its mode of action including its role in regulating MMP1. Importantly, P4HA1 mediated invasion in cancer cells could be reversed using MMP1 inhibitor, revealing therapeutic utility of targeting P4HA1 either directly or by inhibiting its downstream effectors.
2015-05-10 | GSE55787 | GEO
Project description:Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra- and/or intracellular changes. In this study, we observed that one of the ATFs Activating transcription factor 3 (ATF3) is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. Additionally, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion conducive extracellular matrix (ECM) under hypoxic condition. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. It is interesting to note that ATF3's involvement in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Further, we also show that the demethylated DNA region of intron 9a then becomes accessible to CTCF. Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA PolII pause via CTCF at the intron 9a leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results provide a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can be potentially exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion.
2024-12-31 | GSE274936 | GEO
Project description:Metabolic syndrome represents a risk factor of pancreatic ductal adenocarcinoma (PDAC), the gastrointestinal cancer with the lowest survival rate and therapeutic outcome. PDAC results bidirectional interconnected with metabolic alteration, which favors its onset and occurs during early phases of its development. Pancreatic neoplastic lesions evolve within a highly dense desmoplastic stroma, characterized by abundant extracellular matrix deposition consequence of a prominent cancer associated fibroblast (CAF) activation. Here, the complex association between dysmetabolism and PDAC has been analyzed with a specific focus on CAFs to unveil novel targets exploitable for diagnostic and therapeutic purposes. Methods: PDAC development upon dysmetabolic conditions was investigated in: 1) wild type immunocompetent syngeneic mice by orthotopic transplantation of PanIN-bearing Pdx1-Cre; Kras+/LSL-G12D; Trp53+/LSL-R172H organoids (KPC mice) fed with high fat diet to recapitulate dysmetabolism-dependent alterations; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with or without an history of metabolic syndrome. Results: The dysmetabolic-associated higher PDAC aggressiveness was paralleled by an enrichment of collagen fibrils due to an increased function of the prolyl 4-hydroxylase subunit alpha 1 (P4HA1). Upon dysmetabolic conditions, P4HA1 boosts collagen hydroxy-prolination, intensifying collagen contraction strength and thus preventing CD3 positive lymphocyte PDAC infiltration. Interestingly, semaglutide, an incretin agonist with anti-diabetic and anti-obesity properties, is able to prevent the higher stromal deposition of PDAC observed in dysmetabolic conditions, preventing CAF contraction, allowing immune infiltration and reducing tumor development. Conclusion: These results shed light on novel therapeutic options for PDAC patients affected by metabolic syndrome aimed at pancreatic cancer stroma reshape
2025-01-29 | GSE266899 | GEO
Project description:We assessed the role of prolyl hydroxylase inhibiton using DMOG on angiogenic competance and metabolic reprogramming of endothelial cells.
2022-09-12 | GSE189504 | GEO
Project description:P4HA1 mediates hypoxia-induced invasion in human pancreatic cancer organoids
| PRJNA1232238 | ENA
Project description:P4HA1 mediates hypoxia-induced invasion in human pancreatic cancer organoids
| PRJNA1232239 | ENA
Project description:Microarray analysis was used to identify differentially expressed gene signature in ovarian cancer A224 cells treated with recombinant human ITLN1 protein. MMP1 was found to be significantly upregulated in ITLN1-treated A224 cells. Further studies revealed that MMP1 is an important mediator for the ITLN1 suppression of ovarian cancer cell motility and invasion potential.
2019-09-20 | GSE120245 | GEO
Project description:Genetic deletion of transmembrane prolyl-4-hydroxylase (P4H-TM) in mice leads to increased inflammatory microgliosis and neutrophil infiltration in the cortex after permanent midle cerebral artery occlusion (pMCAO)
2020-11-12 | GSE107127 | GEO
Project description:In this study we analyzed impact of long-term hypoxia on a panel of lymphoma cell lines. Only 2 out of 8 tested lymphoma cell lines (Ramos, and HBL2) survived > 4 weeks under deep hypoxia (1% O2). The hypoxia-adapted (HA) Ramos and HBL2 cells had severely decreased proliferation rate accompanied by complex changes of the transcriptome, proteome, and metabolome. Seahorse analysis demonstrated near complete blockage of both oxidative phosphorylation and glycolytic pathways. Both transcriptome and proteome analyses showed significant downregulation of mitochondrial respiration complexes I and IV, many mitochondrial ribosomal proteins, and increase of proteins regulating glycolysis and mitophagy. Both HA cell lines had an increased total mitochondrial mass, but a decreased mitochondrial DNA content compared to normoxic controls. Sensitivity of HA cells to 2-deoxyglucose, an inhibitor of glycolysis, and to A1155463, a BCL-XL inhibitor were, was markedly increased. Indeed, co-culture on CD40 ligand expressing fibroblasts (that induce BCL-XL expression) significantly increased survival of lymphoma cells under hypoxia. Of note, prolyl hydroxylase P4HA1 involved in the stabilization of hypoxia-induced factor (HIF) 1 alpha was increased in both HA cell lines on both mRNA and protein levels. Transgenic (over)expression of P4HA1 in hypoxia-sensitive MINO cells was associated with increased survival under hypoxia. Our data suggest that under long-term hypoxia, lymphoma cells try to compensate for the decrease in ATP production from the oxidative phosphorylation process by boosting structural machinery of glycolysis, as well as amino-acid recycling by mitophagy, on which they become vitally dependent for survival, and which can be targeted by specific inhibitors. The data also suggest increased dependence of lymphoma cells on BCL-XL under hypoxia. Finally, P4HA1 plausibly represents a novel druggable target for more effective elimination of hypoxia-adapted lymphoma cells.
2025-07-01 | GSE266442 | GEO