SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1 alpha (HIF-1 alpha) via direct interactions during hypoxia

Abstract

Upon shift to a hypoxic environment, cellular HIF-1 alpha protein is stabilized, with a rapid decline in oxygen-sensitive hydroxylation. Several additional post-translational modifications of HIF-1 alpha are critical in controlling protein stability during hypoxia. In the present study, we showed that SIRT1 stabilizes HIF-1 alpha via direct binding and deacetylation during hypoxia. SIRT1 depletion or inactivation led to reduced hypoxic HIF-1 alpha accumulation, accompanied by an increase in HIF-1 alpha acetylation. Impaired HIF-1 alpha accumulation was recovered upon inhibition of 26S proteasome activity, indicating that SIRT1 is essential for HIF-1 alpha stabilization during hypoxia. Consistently, HIF-1 alpha accumulation was enhanced upon overexpression of wild-type SIRT1, but not its dominant-negative form. SIRT1-mediated accumulation of HIFI a protein led to increased expression of HIF-1 alpha target genes, including VEGF, GLUT1 and MMP2, and ultimate promotion of cancer cell invasion. These findings collectively imply that hypoxic HIF-1 alpha stabilization requires SIRT1 activation. Furthermore, SIRT1 protection of HIF-1 alpha from acetylation may be a prerequisite for stabilization and consequent enhancement of cell invasion. (C) 2015 Elsevier Inc. All rights reserved.