ArticleCell death & disease2025
USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review).International journal of molecular medicine · 2026Review
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications.Journal of hematology & oncology · 2026Review
- Large-scale transcriptome analysis reveals KIF20A as a novel indicator of cisplatin resistance in high-grade serous ovarian cancer.Journal of ovarian research · 2026Article
- Bosutinib Inhibits USP9X to Suppress the Proliferation, Migration, Angiogenesis and Glycolysis of Hepatocellular Carcinoma Cells by Deubiquitinating PLK1.Clinical and experimental pharmacology & physiology · 2026Article
- Deconstructing cancer in 3D: models, mechanisms, and personalized solutions.Molecular cancer · 2026Review
- Ubiquitin-specific proteases in ovarian cancer: molecular mechanisms and therapeutic implications.Journal of ovarian research · 2026Review
- Decoding ferroptosis and apoptosis crosstalk in glioblastoma: molecular mechanisms, microenvironmental regulation, and therapeutic advances.Molecular biology reports · 2026Review
- Inflammatory milieu and role of epigenetic modifications in high-grade serous ovarian cancer.Clinical epigenetics · 2026Review
- Normalizing the Tumor Microenvironment: A New Frontier in Ovarian Cancer Therapy.International journal of molecular sciences · 2026Review
- Comprehensive analysis of the TGF-β signaling pathway: molecular mechanisms, disease drivers, and frontiers in clinical translation.Frontiers in immunology · 2026Review
- The resilient subset: cancer stem cells at the core of immunotherapy resistance.Immunotherapy advances · 2026Review
- Natural compounds targeting glycolysis and TME in ovarian cancer: from metabolic crosstalk to therapeutic potential.Frontiers in pharmacology · 2026Review
- Role of the tumor microenvironment in chemotherapy resistance in ovarian cancer and targeted therapy.Journal of ovarian research · 2025Review
- Current Research on the Control Mechanisms of Cell Survival and Proliferation as Potential Interaction Sites with Pentacyclic Triterpenoids in Ovarian Cancer.International journal of molecular sciences · 2025Review
- Transcriptomic Profiling of Hypoxia-Adaptive Responses in Tibetan Goat Fibroblasts.Animals : an open access journal from MDPI · 2025Article
- Bidirectional crosstalk between sleep disorders and gynecological cancers: unraveling molecular synergies and precision therapeutics.Frontiers in medicine · 2025Review
- Role of Ubiquitin-regulated EMT in Cancer Metastasis and Chemoresistance.International journal of biological sciences · 2025Review
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12 authors.
Funding
Abstract
Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy-related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-β signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-β signaling to promote HIF-2α positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-β downstream effector, stabilizes HIF-2ɑ in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-β signals converge on USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses. Clinically, USP9X expression correlates with TGF-β signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient-derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-β signaling, and a downstream USP9X-HIF-2ɑ proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-β signaling in CSCs and meliorate clinical chemoresistance.
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