ArticleOncogene2016
H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK.
Article in Oncogene, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.Biochemical Society transactions · 2021Pooled it
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- UPR-induced intracellular C5aR1 promotes adaptation to the hypoxic tumour microenvironment.Cell death & disease · 2025Article
- Histone H3K9 Methylation Is Differentially Modified in Odontogenic Cyst and Tumors.European journal of dentistry · 2025Article
- Exploring the Influence of Metabolic Changes in Fibrotic Lung Diseases.Pulmonary circulation · 2025Review
- Histone H3 lysine 9 tri-methylation is associated with pterygium.BMC ophthalmology · 2025Article
- SETDB1 amplification in osteosarcomas: Insights from its role in healthy tissues and other cancer types.Oncotarget · 2025Review
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- Astrocyte KDM4A mediates chemokines and drives neutrophil infiltration to aggravate cerebral ischemia and reperfusion injury.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer.Genes & diseases · 2024Article
- Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.The Journal of clinical investigation · 2023Article
- Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops.Nucleic acids research · 2023Article
- Maternal tamoxifen exposure leads to abnormal primordial follicle assembly.Histochemistry and cell biology · 2023Article
- Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation.Molecular oncology · 2023Article
- PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers.Molecular oncology · 2023Article
- Hippo signaling and histone methylation control cardiomyocyte cell cycle re-entry through distinct transcriptional pathways.PloS one · 2023Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Regions of hypoxia occur in most solid tumors, and they are associated with a poor prognostic outcome. Despite the absence of detectable DNA damage, severe hypoxia (<0.1% O2) induces a DNA damage response, including the activation of p53 and subsequent induction of p53-dependent apoptosis. Factors affecting hypoxia-induced p53-dependent apoptosis are unclear. Here we asked whether H3K9me3, through mediating gene repression, could regulate hypoxia-induced p53-dependent apoptosis. Under hypoxic conditions, increases in H3K9me3 occur in an oxygen-dependent but HIF-1-independent manner. We demonstrate that under hypoxic conditions, which induce p53 activity, the negative regulator of p53, APAK, is repressed by increases in H3K9me3 along the APAK loci. APAK repression in hypoxia is mediated by the methyltransferase SETDB1 but not Suv39h1 or G9a. Interestingly, increasing hypoxia-induced H3K9me3 through pharmacological inhibition of JMJD2 family members leads to an increase in apoptosis and decreased clonogenic survival and again correlates with APAK expression. The relevance of understanding the mechanisms of APAK expression regulation to human disease was suggested by analysis of patients with colorectal cancer, which demonstrates that high APAK expression correlates with poor prognosis. Together, these data demonstrate the functional importance of H3K9me3 in hypoxia, and they provide a novel mechanistic link between H3K9me3, p53 and apoptosis in physiologically relevant conditions of hypoxia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.