SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation.
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Seo KS, Park JH, Heo JY, Jing K, Han J, Min KN, Kim C, Koh GY, Lim K, Kang GY, Uee Lee J, Yim YH, Shong M, Kwak TH, Kweon GR
SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation.
Oncogene. 2015 Mar 12;34(11):1354-62. doi: 10.1038/onc.2014.76. Epub 2014 Mar 31.
- PubMed ID
- 24681946 [ View in PubMed]
- Abstract
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1alpha 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-1alpha regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1alpha under hypoxic conditions, whereas HIF-1alpha protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1alpha and deacetylated Lys709 of HIF-1alpha. Deacetylation of HIF-1alpha by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1alpha stability, and increased HIF-1alpha hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1alpha by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1alpha deacetylation is critical for the destablization of HIF-1alpha and the hypoxic response of tumour cells.