ArticleThe Journal of clinical investigation2023
AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- TMEM92 shields DDX3X from TTC3-mediated degradation to confer chemoresistance in triple-negative breast cancer.Clinical and translational medicine · 2026Article
- Synaptic aging and neurodegeneration: the role of synaptic vesicle dynamics and neurotransmitter imbalance.Biogerontology · 2026Review
- Age-driven dysbiosis: gut microbiota in the pathogenesis and treatment of aging disorders.Biogerontology · 2026Review
- Structural and functional perspectives on DEAD-box RNA helicases in the rubber tree cold stress response.Frontiers in plant science · 2026Review
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- RNA binding protein DDX3X drives pancreatic cancer progression via the TLE2-MYL9 axis.Science advances · 2025Article
- Targeting PGE2 mediated senescent neuron improves tumor therapy.Neuro-oncology · 2025Article
- Protease regulation of tumor-immune cell symbiosis.Trends in cancer · 2025Review
- β-suppressor protein 1 (ARRB1)-△exon13 modulates the progression of glioblastoma via combination with glycolysis-related proteins.Biochemistry and biophysics reports · 2025Article
- LSM12 promotes the lung squamous cell carcinoma progression through mediating alternative splicing of ARRB1.Communications biology · 2025Article
- Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models.The Journal of clinical investigation · 2025Article
- Intranasal delivery of AEP inhibitor-loaded neuron-targeted liposome ameliorates radiation-induced brain injury.Materials today. Bio · 2025Article
- Opportunities and challenges for patient-derived models of brain tumors in functional precision medicine.NPJ precision oncology · 2025Review
- Article
- Review
- The alternatively spliced diacylglycerol kinase gamma-Δ exon13 transcript generated under hypoxia promotes glioblastoma progression.Oncology research · 2025Article
- Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme.Cell death & disease · 2024Review
- Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.iScience · 2024Article
- AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors.The Journal of clinical investigation · 2024Article
- Multifunctional role of DEAD-box helicase 41 in innate immunity, hematopoiesis and disease.Frontiers in immunology · 2024Review
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation-induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many pre-mRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-Δexon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1-Δexon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets.
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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.