Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 462, Issue 4, Pages 294-300Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2015.04.119
Keywords
SIRT1; HIF-1 alpha; Stabilization; Deacetylation; Interaction; Invasion
Categories
Funding
- National Research Foundation of Korea [NRF-2012R1A1A2008457, NRF-2012M3A9B6055346, NRF-2014M3A9A8064818, NRF-2012R1A2A1A01009027]
- National Nuclear R&D program of the Ministry of Science and Technology
- Ministry of Science, ICT & Future Planning, Republic of Korea [505152015] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2012M3A9B6055346, 2012R1A2A1A01009027, 21A20131212485, 2014M3A9A8064818] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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