Abstract Upon shift to a hypoxic environment, cellular HIF-1α protein is stabilized, with a rapid decline in oxygen-sensitive hydroxylation. Several additional post-translational modifications of HIF-1α are critical in controlling protein stability during hypoxia. In the present study, we showed that SIRT1 stabilizes HIF-1α via direct binding and deacetylation during hypoxia. SIRT1 depletion or inactivation led to reduced hypoxic HIF-1α accumulation, accompanied by an increase in HIF-1α acetylation. Impaired HIF-1α accumulation was recovered upon inhibition of 26S proteasome activity, indicating that SIRT1 is essential for HIF-1α stabilization during hypoxia. Consistently, HIF-1α accumulation was enhanced upon overexpression of wild-type SIRT1, but not its dominant-negative form. SIRT1-mediated accumulation of HIF-1α protein led to increased expression of HIF-1α target genes, including VEGF, GLUT1 and MMP2, and ultimate promotion of cancer cell invasion. These findings collectively imply that hypoxic HIF-1α stabilization requires SIRT1 activation. Furthermore, SIRT1 protection of HIF-1α from acetylation may be a prerequisite for stabilization and consequent enhancement of cell invasion.
|Number of pages||7|
|Journal||Biochemical and biophysical research communications|
|Publication status||Published - 2015 Jun 12|
Bibliographical noteFunding Information:
This work was supported by grants from the National Research Foundation of Korea ( NRF-2012R1A1A2008457 , NRF-2012M3A9B6055346 , NRF-2014M3A9A8064818 and NRF-2012R1A2A1A01009027) and National Nuclear R&D program of the Ministry of Science and Technology .
© 2015 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology