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

• Published in: Oncogene Vol. 34; no. 11; p. 1354
• Main Authors: Seo, K-s, Park, J-h, Heo, J-y, Jing, K, Han, J, Min, K-n, Kim, C, Koh, G Y, Lim, K, Kang, G-y, Uee Lee, J, Yim, Y-h, Shong, M, Kwak, T-h, Kweon, G R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 12.03.2015
• Subjects: Cancer; Cellular biology; Metabolism; Studies
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.76

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1 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 regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1 under hypoxic conditions, whereas HIF-1 protein levels were high in SIRT2-decient cells. SIRT2 directly interacted with HIF-1 and deacetylated Lys709 of HIF-1. Deacetylation of HIF-1 by SIRT2 resulted in increased binding afnity for prolyl hydroxylase 2, a key regulator of HIF-1 stability, and increased HIF-1 hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD+/NADH ratio led to the degradation of HIF-1 by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These ndings suggest that SIRT2-mediated HIF-1 deacetylation is critical for the destablization of HIF-1 and the hypoxic response of tumour cells.