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

  • Oncogene. 2015 Mar 12;34(11):1354-62. doi: 10.1038/onc.2014.76.
K-S Seo  1 ,  J-H Park  1 ,  J-Y Heo  2 ,  K Jing  2 ,  J Han  2 ,  K-N Min  3 ,  C Kim  4 ,  G Y Koh  4 ,  K Lim  5 ,  G-Y Kang  6 ,  J Uee Lee  7 ,  Y-H Yim  8 ,  M Shong  9 ,  T-H Kwak  3 ,  G R Kweon  1
Affiliations
  • 1. Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea.
  • 2. 1] Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
  • 3. KT&G Life Sciences Corp. R&D Center, Suwon, Korea.
  • 4. National Research Laboratory of Vascular Biology and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  • 5. 1] Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea [3] Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Korea.
  • 6. Diatech Korea Co., Ltd, Seoul, Korea.
  • 7. Department of Pathology, St. Mary's Hospital, The Catholic University, Daejeon, Korea.
  • 8. Korea Research Institute of Standard and Science, Daejeon, Korea.
  • 9. Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.
PMID: 24681946 DOI: 10.1038/onc.2014.76
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.