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RSUME inhibits VHL and regulates its tumor suppressor function

Oncogene volume 34, pages 4855–4866 (2015)Cite this article

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Abstract

Somatic mutations or loss of von Hippel–Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.

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Acknowledgements

We thank Sergio Senin, María Antunica Noguerol, Jimena Druker and Mariana Haedo for technical help. We also thank the Argentinian Instituto Nacional del Cáncer (INC) and Bunge&Born Foundation for financial support to Lucas Tedesco and Juan Jose Bonfiglio, respectively. This work was supported by grants from the Max Planck Society, Germany; the University of Buenos Aires; CONICET; the Agencia Nacional de Promoción Científica y Tecnológica, Argentina and FOCEM-Mercosur (COF 03/11).

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  1. J Gerez and L Tedesco: These authors equally contributed to this work.

Authors and Affiliations

  1. Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)—CONICET—Partner Institute of the Max Planck Society, Buenos Aires, Argentina

    J Gerez, L Tedesco, J J Bonfiglio, M Fuertes, S Silberstein & E Arzt

  2. Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

    J Gerez, J J Bonfiglio, S Silberstein & E Arzt

  3. Center for Endocrinological Investigations (CEDIE), Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina

    M Barontini

  4. Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany

    Y Wu, U Renner, M Páez-Pereda, F Holsboer & G K Stalla

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Gerez, J., Tedesco, L., Bonfiglio, J. et al. RSUME inhibits VHL and regulates its tumor suppressor function. Oncogene 34, 4855–4866 (2015). https://doi.org/10.1038/onc.2014.407

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