ArticleNature cell biology2017
A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.
Article in Nature cell biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 59 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 106 citations in OpenAlex.
- E3 Ubiquitin Ligases in Breast Cancer Metastasis: A Systematic Review of Pathogenic Functions and Clinical Implications.Frontiers in oncology · 2021Pooled it
- A non-canonical function of RNF8 opposes TRAF6-mediated stabilization of HIF1α.RSC chemical biology · 2026Article
- Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen.Molecular cell · 2025Article
- Article
- Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- PRMT5 regulates alternative splicing of TCF3 under hypoxia to promote EMT and invasion in breast cancer.PLoS biology · 2025Article
- RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α.Nature communications · 2025Article
- Molecular signaling and clinical implications in the human aging-cancer cycle.Seminars in cancer biology · 2024Review
- Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment.Cancer communications (London, England) · 2024Review
- Article
- Transcriptional elongation control of hypoxic response.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Activation of RhoA/ROCK2 signaling by hypoxia-inducible factor 1α in promoting tumor growth and metastasis in human colon cancer.Journal of gastrointestinal oncology · 2024Article
- DNA damage signalling histone H2AX is required for tumour growth.Cell death discovery · 2024Article
- Multi-omics analyses of choroid plexus carcinoma cell lines reveal potential targetable pathways and alterations.Journal of neuro-oncology · 2024Article
- Tumor Necrosis Factor Receptor-Associated Factor 6 and Human Cancer: A Systematic Review of Mechanistic Insights, Functional Roles, and Therapeutic Potential.Journal of Cancer · 2024Review
- Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy.Aging cell · 2024Article
- Acetylation and Phosphorylation in the Regulation of Hypoxia-Inducible Factor Activities: Additional Options to Modulate Adaptations to Changes in Oxygen Levels.Life (Basel, Switzerland) · 2023Review
- Article
- CXCR1 drives the pathogenesis of EAE and ARDS via boosting dendritic cells-dependent inflammation.Cell death & disease · 2023Article
- Cyclers' kinases in cell division: from molecules to cancer therapy.Cell death and differentiation · 2023Review
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
Abstract
The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumorigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy.
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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.