ArticleGenes & development2015
Hypoxia drives transient site-specific copy gain and drug-resistant gene expression.
Article in Genes & development, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Pooled it
- Hypoxia-induced metastatic heterogeneity in pancreatic cancer.Nature communications · 2026Article
- Mechano-stress endorsing heterogeneous lung cancer cells migration into confined channels and investigating tumor spheroids growth of confined space migrating cells.Scientific reports · 2026Article
- Epigenotoxicity: Decoding the epigenetic imprints of genotoxic agents and their implications for regulatory genetic toxicology.Environmental and molecular mutagenesis · 2025Review
- Hypoxia-induced metastatic heterogeneity in pancreatic cancer.Research square · 2025Article
- Review
- Proteogenomic discovery ofScience advances · 2025Article
- Targeting N-Methyl-lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery.ChemMedChem · 2025Review
- Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.Genes & development · 2024Review
- The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities.Genes & diseases · 2024Review
- Article
- Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma.Cancer medicine · 2023Review
- Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome.Signal transduction and targeted therapy · 2023Review
- Chronic hypoxia is associated with transcriptomic reprogramming and increased genomic instability in cancer cells.Frontiers in cell and developmental biology · 2023Article
- Chromosomal Instability, Selection and Competition: Factors That Shape the Level of Karyotype Intra-Tumor Heterogeneity.Cancers · 2022Review
- DNA repair as a shared hallmark in cancer and ageing.Molecular oncology · 2022Review
- Recent Advances with KDM4 Inhibitors and Potential Applications.Journal of medicinal chemistry · 2022Review
- Article
- Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.International journal of molecular sciences · 2022Review
- Diverse Epigenetic Regulations of Macrophages in Atherosclerosis.Frontiers in cardiovascular medicine · 2022Review
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Authors and funding
18 authors at 6 institutions in 1 country.
Funding
Abstract
Copy number heterogeneity is a prominent feature within tumors. The molecular basis for this heterogeneity remains poorly characterized. Here, we demonstrate that hypoxia induces transient site-specific copy gains (TSSGs) in primary, nontransformed, and transformed human cells. Hypoxia-driven copy gains are not dependent on HIF1α or HIF2α; however, they are dependent on the KDM4A histone demethylase and are blocked by inhibition of KDM4A with a small molecule or the natural metabolite succinate. Furthermore, this response is conserved at a syntenic region in zebrafish cells. Regions with site-specific copy gain are also enriched for amplifications in hypoxic primary tumors. These tumors exhibited amplification and overexpression of the drug resistance gene CKS1B, which we recapitulated in hypoxic breast cancer cells. Our results demonstrate that hypoxia provides a biological stimulus to create transient site-specific copy alterations that could result in heterogeneity within tumors and cell populations. These findings have major implications in our understanding of copy number heterogeneity and the emergence of drug resistance genes in cancer.
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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.