ArticleClinical epigenetics2021
Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner.
Article in Clinical epigenetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 57 citations in OpenAlex.
- Evaluation of translational potential of mRNA vaccine candidate antigens for pancreatic cancer: a systematic review based on clinical evidence and stratified prioritization strategies.Frontiers in immunology · 2026Pooled it
- The Crosstalk Between Metabolic Reprogramming and Histone Methylation in Tumor Immunity and Immunotherapy.Cells · 2026Review
- Post-Translational Modifications in Pancreatic Cancer: Mechanisms to Clinical Applications.Journal of gastroenterology and hepatology · 2026Review
- ALDH1A3 promotes the lung metastatic organotropism of pancreatic ductal adenocarcinoma through semaphorin signaling.iScience · 2026Article
- Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review).International journal of oncology · 2026Review
- BRD4 Inhibition alleviates sepsis-associated acute kidney injury via suppression of NOX4-mediated oxidative stress and inflammation.Cell death discovery · 2026Article
- Epigenetic regulation in cancer metastasis.Discover oncology · 2026Review
- Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma.Frontiers in cell and developmental biology · 2026Article
- CD73 is associated with glycolysis related metabolic programs and CD8Frontiers in immunology · 2026Article
- The central role of EMT in tumor progression: mechanistic drivers, biomarker discovery, and therapeutic horizons.Frontiers in pharmacology · 2026Review
- Analysis of an engineered organoid model of pancreatic cancer identifies hypoxia as a contributing factor in determining transcriptional subtypes.Scientific reports · 2025Article
- NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer.Current medical science · 2025Article
- Epigenetic dysregulation in pancreatic cancer: emerging biomarkers and clinical applications.Frontiers in epigenetics and epigenomics · 2025Review
- Targeting stromal components in pancreatic ductal adenocarcinoma: a review.Ecancermedicalscience · 2025Review
- Strategies for Pancreatic Cancer-Responsive Nanodrug Platforms Targeting Tumor Hypoxic Environments.International journal of nanomedicine · 2025Review
- Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases: Mechanisms and future perspectives.World journal of gastroenterology · 2024Review
- Unraveling the interplay: exploring signaling pathways in pancreatic cancer in the context of pancreatic embryogenesis.Frontiers in cell and developmental biology · 2024Review
- Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma.Redox biology · 2023Article
- Inkjet-printed morphogenesis of tumor-stroma interface using bi-cellular bioinks of collagen-poly(N-isopropyl acrylamide-co-methyl methacrylate) mixture.Materials today. Advances · 2023Article
- Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma.Molecular cancer · 2023Review
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored.
methodsA hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism.
resultsWe quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT.
conclusionsThis study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.
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