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SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation

Oncogene volume 34, pages 1354–1362 (2015)Cite this article

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production and promotes tumour growth. Sirtuins are NAD+-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD+/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells.

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Acknowledgements

We thank Dr HS Kim, Dr JH Lim and Dr JW Park for their skillful methodological assistance, Dr JJ Lee for the HRE luciferase plasmid and Dr KY Lee for the SIRT2 expression plasmids. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2009-1176023, 2011-0011365) (GRK) and the NRF funded by the Ministry of Science, ICT & Future Planning (2007-0054932).

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Author notes

  1. K-S Seo and J-H Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea,

    K-S Seo, J-H Park, J-Y Heo, K Jing, J Han, K Lim & G R Kweon

  2. Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea,

    J-Y Heo, K Jing, J Han & K Lim

  3. KT&G Life Sciences Corp. R&D Center, Suwon, Korea

    K-N Min & T-H Kwak

  4. National Research Laboratory of Vascular Biology and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea

    C Kim & G Y Koh

  5. Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Korea,

    K Lim

  6. Diatech Korea Co., Ltd, Seoul, Korea

    G-Y Kang

  7. Department of Pathology, St. Mary’s Hospital, The Catholic University, Daejeon, Korea

    J Uee Lee

  8. Korea Research Institute of Standard and Science, Daejeon, Korea

    Y-H Yim

  9. Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea

    M Shong

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Correspondence to T-H Kwak or G R Kweon.

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Seo, KS., Park, JH., Heo, JY. et al. SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation. Oncogene 34, 1354–1362 (2015). https://doi.org/10.1038/onc.2014.76

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