| First Author | Seo KS | Year | 2015 |
| Journal | Oncogene | Volume | 34 |
| Issue | 11 | Pages | 1354-62 |
| PubMed ID | 24681946 | Mgi Jnum | J:211313 |
| Mgi Id | MGI:5574427 | Doi | 10.1038/onc.2014.76 |
| Citation | Seo KS, et al. (2015) SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene 34(11):1354-62 |
| abstractText | 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. |
