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Updated: Jan 27, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME
Lucas Tedesco1, Belén Elguero1, David Gonilski Pacin1
1Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Godoy Cruz 2390, C1425FQD, Buenos Aires, Argentina.
Abstract:
Renal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease. Resistance to therapies targeting tumor angiogenesis opens the question about the underlying mechanisms. Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice. In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations. We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors. Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis. The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2α-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex. Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors.
Insights
RSUME protein promotes renal cell carcinoma (RCC) growth in von Hippel-Lindau (VHL) disease by stabilizing HIF. Targeting RSUME reduces tumor angiogenesis in VHL-mutated RCC, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Renal cell carcinoma (RCC) is a significant cause of mortality in von Hippel-Lindau (VHL) disease patients.
- Therapeutic resistance in RCC suggests underlying mechanisms related to tumor angiogenesis.
- Previous work identified RSUME (RWD domain-containing protein SUMO Enhancer) as a regulator of VHL protein and HIF degradation, impacting RCC growth.
Purpose of the Study:
- To investigate the role of RSUME in the development and progression of VHL-mutated RCC.
- To elucidate the molecular mechanisms by which RSUME contributes to the angiogenic phenotype in VHL-mutated RCC.
- To evaluate RSUME as a potential therapeutic target for VHL-mutated RCC.
Main Methods:
- Bioinformatic analysis of a clear cell RCC (ccRCC) dataset to correlate RSUME levels with VHL mutations and tumor progression.
- In vitro studies to demonstrate the molecular interactions between RSUME, VHL mutants, and HIF.
- Assessment of tumor angiogenesis in RCC cell line clones with VHL mutations after RSUME targeting.
Main Results:
- RSUME levels are associated with VHL mutations and tumor progression in ccRCC.
- VHL mutants exhibit impaired downregulation of RSUME, leading to increased RSUME expression in RCC tumors.
- Targeting RSUME in VHL-mutated RCC cell lines significantly decreased early tumor angiogenesis.
- RSUME directly interacts with VHL mutants, affecting HIF-2α binding and the assembly of the VHL-Elongins-Cullins (ECV) complex.
Conclusions:
- RSUME plays a critical role in the deregulation of VHL mutants, driving the angiogenic phenotype in RCC.
- The findings highlight RSUME as a key mediator of pathological angiogenesis in VHL-mutated RCC.
- RSUME inhibition presents a promising therapeutic strategy for VHL-mutated RCC by reducing tumor angiogenesis.
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