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

Abstract

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.