ArticleThe EMBO journal2024
VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
What it found
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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
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Hyperprogressive disease in carcinoma induced by immune checkpoint inhibitor therapy: a systematic review.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Pooled it
- Review
- Article
- PHD1-dependent hydroxylation of RepoMan (CDCA2) on P604 modulates the control of mitotic progression.eLife · 2026Article
- Von Hippel-Lindau disease: pathophysiological and clinical advances.Familial cancer · 2026Review
- AMPK-activated BAP1 regulates pVHL stability and tumor-suppressive functions.Cell death and differentiation · 2026Article
- Article
- Construction and verification of a prognostic model of neutrophil-related genes in clear cell renal cell carcinoma.Translational andrology and urology · 2026Article
- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Article
- Porcine Beclin1 facilitates the proliferation of porcine circovirus type 2 by augmenting autophagy in PK-15 cells.Frontiers in cellular and infection microbiology · 2026Article
- SRAS1.1 E3 ligase mediates DSK2A degradation to regulate autophagy and drought tolerance in Arabidopsis.EMBO reports · 2025Article
- VHL-Mediated SYT11 Degradation Suppresses Gastric Cancer Cell Growth and Invasion Through Downregulation of SPINK1.Journal of cellular and molecular medicine · 2025Article
- Review
- Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.Molecular oncology · 2025Article
- Roles of E3 ubiquitin ligases and deubiquitinating enzymes in renal cell carcinoma.Frontiers in oncology · 2025Review
- JNK signaling mediates acute rejection via activating autophagy of CD8Frontiers in immunology · 2024Article
- STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma.Research (Washington, D.C.) · 2024Article
- Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis.Frontiers in immunology · 2024Review
Corrections and comments
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Authors and funding
21 authors at 4 institutions in 1 country.
Funding
Abstract
The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.
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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.