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

被引:108
作者
Seo, K-S [1 ]
Park, J-H [1 ]
Heo, J-Y [1 ,2 ]
Jing, K. [1 ,2 ]
Han, J. [1 ,2 ]
Min, K-N [3 ]
Kim, C. [4 ,5 ]
Koh, G. Y. [4 ,5 ]
Lim, K. [1 ,2 ,6 ]
Kang, G-Y [7 ]
Lee, J. Uee [8 ]
Yim, Y-H [9 ]
Shong, M. [10 ]
Kwak, T-H [3 ]
Kweon, G. R. [1 ]
机构
[1] Chungnam Natl Univ, Sch Med, Dept Biochem, Taejon 301747, South Korea
[2] Chungnam Natl Univ, Sch Med, Infect Signaling Network Res Ctr, Taejon 301747, South Korea
[3] KT&G Life Sci Corp R&D Ctr, Suwon, South Korea
[4] Korea Adv Inst Sci & Technol, Natl Res Lab Vasc Biol, Taejon 305701, South Korea
[5] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Taejon 305701, South Korea
[6] Chungnam Natl Univ, Sch Med, Canc Res Inst, Taejon 301747, South Korea
[7] Diatech Korea Co Ltd, Seoul, South Korea
[8] Catholic Univ, St Marys Hosp, Dept Pathol, Taejon, South Korea
[9] Korea Res Inst Standard & Sci, Taejon, South Korea
[10] Chungnam Natl Univ, Sch Med, Dept Internal Med, Taejon 301747, South Korea
基金
新加坡国家研究基金会;
关键词
INDUCIBLE FACTOR-1-ALPHA; OXIDOREDUCTASE; METABOLISM; HIF1-ALPHA; DEGRADATION; ACTIVATION; PROTEIN; ACETYLATION; SUPPRESSION; OXIDATION;
D O I
10.1038/onc.2014.76
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1 alpha 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-1 alpha regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1 alpha under hypoxic conditions, whereas HIF-1 alpha protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1 alpha and deacetylated Lys709 of HIF-1 alpha. Deacetylation of HIF-1 alpha by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1a stability, and increased HIF-1 alpha hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1 alpha by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1 alpha deacetylation is critical for the destablization of HIF-1 alpha and the hypoxic response of tumour cells.
引用
收藏
页码:1354 / 1362
页数:9
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