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.

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