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Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Oncogene volume 31, pages 1065–1072 (2012)Cite this article

Abstract

Inactivation of the von Hippel–Lindau (VHL) tumor suppressor gene underlies the majority of sporadic clear cell renal cell carcinomas (CCRCCs) and is also responsible for the hereditary VHL cancer syndrome. VHL loss of function results in constitutive stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) due to insufficient proteolysis in the presence of oxygen. This activates multiple genes relevant to tumorigenesis, allowing cells to acquire further mutations and undergo malignant transformation. However, the specific role of each HIF-α subunit in CCRCC tumorigenesis is not yet well understood. The current paradigm supports that in the first stages of CCRCC formation the stabilization of HIF-1α is dominant and this limits proliferation, but later on HIF-2α increases and this induces a more aggressive cell behavior. Understanding how this transition happens is highly relevant, as it may provide novel ways to treat these cancers. Here, we show that VHL inactivation in CCRCC cells results in HIF-1α/2α-dependent downregulation of HIF-1α mRNA through direct binding of either subunit to a reverse hypoxia-response element in the HIF-1α proximal promoter. This binding activates a series of repressive histone modification marks including histone 3 lysine 27 trimethylation (H3K27me3) to make the changes stable, and if overturned reduces CCRCC cell proliferation due to excessive HIF-1α expression level. Our findings thus help understand how HIF-α subunits influence each other and also reinforce the idea that epigenetic mechanisms are a key step of CCRCC progression.

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Acknowledgements

This work was supported by start-up funding from the Guangzhou Institutes of Biomedicine and Health and the Chinese Academy of Sciences Grant KSCX2-YW-R-244 to MAE. We thank Dr Duanqing Pei for his constant support.

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Authors and Affiliations

  1. Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

    J Xu, B Wang, Y Xu, L Sun, W Tian & M A Esteban

  2. Centre for Cell Signaling and Molecular Genetics, Rayne Institute, University College London, London, UK

    D Shukla, R Barod & P H Maxwell

  3. Department of Biotechnology, Aging and Immortalization Research, University of Natural Resources and Life Sciences, Vienna, Austria

    J Grillari & R Grillari-Voglauer

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  1. J Xu
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  2. B Wang
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Correspondence to M A Esteban.

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Xu, J., Wang, B., Xu, Y. et al. Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element. Oncogene 31, 1065–1072 (2012). https://doi.org/10.1038/onc.2011.305

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