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  • Original Article
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Mutant versions of von Hippel-Lindau (VHL) can protect HIF1α from SART1-mediated degradation in clear-cell renal cell carcinoma

Oncogene volume 35, pages 587–594 (2016)Cite this article

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Abstract

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor drives the development of clear-cell renal cell carcinoma (ccRCC) through hypoxia-inducible factors (HIFs). Although ccRCC cells exhibit constitutive normoxic HIF signaling, the potential role of hypoxia in this setting is not fully understood. We show here that the ccRCC cell lines RCC4 and RCC10, which express mutant versions of VHL, have reduced HIF1α expression in hypoxia, whereas HIF2α expression is increased or not affected. Similar findings were observed in normoxia after abrogation of prolyl hydroxylase activity by siRNA or pharmacological inhibition, and by siRNA inhibition of mutant VHL. This reduction of HIF1α protein is due to proteasome-dependent degradation and is mediated by the E3 ubiquitin ligase SART1. HIF1α degradation favors ccRCC proliferation, in line with the previously recognized tumor suppressor capability of HIF1α. Our data indicate that mutant VHL can protect HIF1α from SART1-dependent degradation in normoxic conditions, but this protection is lost in hypoxic settings, favoring hypoxia-dependent ccRCC proliferation. This mechanism of HIF1α degradation might operate in some VHL-related clear-cell renal carcinomas in which the deletion of HIF1α locus does not occur.

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Acknowledgements

This work was supported by MINECO (SAF 2010-14851), MINECO (SAF 2013-48130), Recava Network (RD12/0042/0065), Programa Prometeo Government of Ecuador and Metoxia Project-Health (F2 2009-222741) to MOL; Consepoc (S2014/BMD-2542 consepoc-CM) and MICINN (SAF 2011-29716) to JA. We thank M. Ohh (Laboratory Medicine & Pathobiology University of Toronto) for providing the RCC10 cell line.

Author Contributions

AON, JA and MOL designed the research; AON, EF, BAI and AE performed the research; AON, EB, JA and MOL wrote the paper.

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Author notes

  1. J Aragonés and M O Landazuri: These authors contributed equally to this work.

Authors and Affiliations

  1. Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain

    Á Ordóñez-Navadijo, E Fuertes-Yebra, B Acosta-Iborra, E Balsa, A Elorza, J Aragonés & M O Landazuri

  2. Universidad Central del Ecuador, Quito, Ecuador

    M O Landazuri

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  1. Á Ordóñez-Navadijo
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  2. E Fuertes-Yebra
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Correspondence to M O Landazuri.

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Ordóñez-Navadijo, Á., Fuertes-Yebra, E., Acosta-Iborra, B. et al. Mutant versions of von Hippel-Lindau (VHL) can protect HIF1α from SART1-mediated degradation in clear-cell renal cell carcinoma. Oncogene 35, 587–594 (2016). https://doi.org/10.1038/onc.2015.113

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