ArticleMolecular cancer research : MCR2019
Hypoxia-Associated Factor (HAF) Mediates Neurofibromin Ubiquitination and Degradation Leading to Ras-ERK Pathway Activation in Hypoxia.
Article in Molecular cancer research : MCR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 30 citations in OpenAlex.
- Neurofibromin 1 (International journal of molecular sciences · 2026Article
- A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/- mice.The Journal of clinical investigation · 2025Article
- Investigating the Mechanism of Emodin in Rheumatoid Arthritis Through the HIF-1α/NLRP3 Pathway and Mitochondrial Autophagy.Current issues in molecular biology · 2025Article
- Review
- Submersion and hypoxia inhibit alveolar epithelial NaRespiratory research · 2023Article
- The therapeutic potential of neurofibromin signaling pathways and binding partners.Communications biology · 2023Review
- NPAS2 promotes aerobic glycolysis and tumor growth in prostate cancer through HIF-1A signaling.BMC cancer · 2023Article
- Hypoxia in Skin Cancer: Molecular Basis and Clinical Implications.International journal of molecular sciences · 2023Review
- Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Radiogenomics study to predict the nuclear grade of renal clear cell carcinoma.European journal of radiology open · 2023Article
- The NEDD8-activating enzyme inhibitor MLN4924 reduces ischemic brain injury in mice.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Effects of Sensitized Sorafenib with a Paeoniflorin and Geniposide Mixture on Liver Cancer via the NF-Evidence-based complementary and alternative medicine : eCAM · 2022Article
- Neurofibromin Deficiency Causes Epidermal Growth Factor Receptor Upregulation through the Activation of Ras/ERK/SP1 Signaling Pathway in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheet Tumor.International journal of molecular sciences · 2021Article
- Hypoxia Transcriptomic Modifications Induced by Proton Irradiation in U87 Glioblastoma Multiforme Cell Line.Journal of personalized medicine · 2021Article
- Review
- Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2020Article
- Review
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7 authors at 3 institutions in 1 country.
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Abstract
Low oxygen or hypoxia is a feature of all solid tumors and has been associated with aggressive disease. Here, we describe a novel mechanism for the hypoxia-dependent degradation of the Ras-GTPase-activating protein neurofibromin, by hypoxia-associated factor (HAF). We have previously characterized HAF as an oxygen-independent ubiquitin ligase for HIF-1α. Here, we show that HAF promotes neurofibromin ubiquitination and degradation independently of oxygen and pVHL, resulting in Ras-ERK pathway activation. Hypoxia enhanced HAF:neurofibromin binding independently of HAF-SUMOylation, whereas HAF knockdown increased neurofibromin levels primarily in hypoxia, supporting the role of HAF as a hypoxia-specific neurofibromin regulator. HAF overexpression increased p-ERK levels and promoted resistance of clear cell kidney cancer (ccRCC) cells to sorafenib and sunitinib in both normoxia and hypoxia. However, a greater-fold increase in sorafenib/sunitinib resistance was observed during hypoxia, particularly in pVHL-deficient cells. Intriguingly, HAF-mediated resistance was HIF-2α-dependent in normoxia, but HIF-2α-independent in hypoxia indicating two potential mechanisms of HAF-mediated resistance: a HIF-2α-dependent pathway dominant in normoxia, and the direct activation of the Ras-ERK pathway through neurofibromin degradation dominant in hypoxia. Patients with ccRCC with high HAF transcript or protein levels showed significantly decreased overall survival compared with those with low HAF. Thus, we establish a novel, nonmutational pathway of neurofibromin inactivation through hypoxia-induced HAF-mediated degradation, leading to Ras-ERK activation and poor prognosis in ccRCC. IMPLICATIONS: We describe a novel mechanism of neurofibromin degradation induced by hypoxia that leads to activation of the prooncogenic Ras-ERK pathway and resistance to therapy.
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