Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 324 (5932): 1289-1293

Copyright © 2009 by the American Association for the Advancement of Science

Regulation of Hypoxia-Inducible Factor 2{alpha} Signaling by the Stress-Responsive Deacetylase Sirtuin 1

Elhadji M. Dioum,1,2,* Rui Chen,1,2,* Matthew S. Alexander,2 Quiyang Zhang,2 Richard T. Hogg,2 Robert D. Gerard,2,3 Joseph A. Garcia1,2,{dagger}

Abstract: To survive in hostile environments, organisms activate stress-responsive transcriptional regulators that coordinately increase production of protective factors. Hypoxia changes cellular metabolism and thus activates redox-sensitive as well as oxygen-dependent signal transducers. We demonstrate that Sirtuin 1 (Sirt1), a redox-sensing deacetylase, selectively stimulates activity of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2{alpha}) during hypoxia. The effect of Sirt1 on HIF-2{alpha} required direct interaction of the proteins and intact deacetylase activity of Sirt1. Select lysine residues in HIF-2{alpha} that are acetylated during hypoxia confer repression of Sirt1 augmentation by small-molecule inhibitors. In cultured cells and mice, decreasing or increasing Sirt1 activity or levels affected expression of the HIF-2{alpha} target gene erythropoietin accordingly. Thus, Sirt1 promotes HIF-2 signaling during hypoxia and likely other environmental stresses.

1 Veterans Affairs North Texas Health Care System, Department of Medicine, 4500 South Lancaster Road, Dallas, TX 75216, USA.
2 University of Texas Southwestern Medical Center at Dallas, Department of Internal Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390–8573, USA.
3 University of Texas Southwestern Medical Center at Dallas, Department of Molecular Biology, 5323 Harry Hines Boulevard, Dallas, TX 75390–8573, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: joseph.garcia{at}

EAF2 Suppresses Hypoxia-Induced Factor 1{alpha} Transcriptional Activity by Disrupting Its Interaction with Coactivator CBP/p300.
Z. Chen, X. Liu, Z. Mei, Z. Wang, and W. Xiao (2014)
Mol. Cell. Biol. 34, 1085-1099
   Abstract »    Full Text »    PDF »
FoxO4 interacts with the sterol regulatory factor SREBP2 and the hypoxia inducible factor HIF2{alpha} at the CYP51 promoter.
J. Zhu, X. Jiang, and F. F. Chehab (2014)
J. Lipid Res. 55, 431-442
   Abstract »    Full Text »    PDF »
SIRT1 Limits the Function and Fate of Myeloid-Derived Suppressor Cells in Tumors by Orchestrating HIF-1{alpha}-Dependent Glycolysis.
G. Liu, Y. Bi, B. Shen, H. Yang, Y. Zhang, X. Wang, H. Liu, Y. Lu, J. Liao, X. Chen, et al. (2014)
Cancer Res. 74, 727-737
   Abstract »    Full Text »    PDF »
NAMPT (visfatin), a direct target of hypoxia-inducible factor-2{alpha}, is an essential catabolic regulator of osteoarthritis.
S. Yang, J.-H. Ryu, H. Oh, J. Jeon, J.-S. Kwak, J.-H. Kim, H. A. Kim, C.-H. Chun, and J.-S. Chun (2013)
Ann Rheum Dis
   Abstract »    Full Text »
Novel Role of Silent Information Regulator 1 in Myocardial Ischemia.
Y. Yang, W. Duan, Y. Li, Z. Jin, J. Yan, S. Yu, and D. Yi (2013)
Circulation 128, 2232-2240
   Full Text »    PDF »
Life-Span Extension From Hypoxia in Caenorhabditis elegans Requires Both HIF-1 and DAF-16 and Is Antagonized by SKN-1.
S. F. Leiser, M. Fletcher, A. Begun, and M. Kaeberlein (2013)
J Gerontol A Biol Sci Med Sci 68, 1135-1144
   Abstract »    Full Text »    PDF »
Hypoxia-Inducible Factor Signaling in Pheochromocytoma: Turning the Rudder in the Right Direction.
I. Jochmanova, C. Yang, Z. Zhuang, and K. Pacak (2013)
J Natl Cancer Inst 105, 1270-1283
   Abstract »    Full Text »    PDF »
PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells.
L. Sun, H. Li, J. Chen, Y. Iwasaki, T. Kubota, M. Matsuoka, A. Shen, Q. Chen, and Y. Xu (2013)
J. Cell Sci. 126, 3939-3947
   Abstract »    Full Text »    PDF »
Sirtuin-7 Inhibits the Activity of Hypoxia-inducible Factors.
M. E. Hubbi, H. Hu, Kshitiz, D. M. Gilkes, and G. L. Semenza (2013)
J. Biol. Chem. 288, 20768-20775
   Abstract »    Full Text »    PDF »
A SUMOylation-Dependent Pathway Regulates SIRT1 Transcription and Lung Cancer Metastasis.
L. Sun, H. Li, J. Chen, V. Dehennaut, Y. Zhao, Y. Yang, Y. Iwasaki, B. Kahn-Perles, D. Leprince, Q. Chen, et al. (2013)
J Natl Cancer Inst 105, 887-898
   Abstract »    Full Text »    PDF »
Sirtuin deacylases: a molecular link between metabolism and immunity.
N. Preyat and O. Leo (2013)
J. Leukoc. Biol. 93, 669-680
   Abstract »    Full Text »    PDF »
Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo.
S. Portmann, R. Fahrner, A. Lechleiter, A. Keogh, S. Overney, A. Laemmle, K. Mikami, M. Montani, M. P. Tschan, D. Candinas, et al. (2013)
Mol. Cancer Ther. 12, 499-508
   Abstract »    Full Text »    PDF »
Emerging Roles of SIRT1 in Cancer Drug Resistance.
Z. Wang and W. Chen (2013)
Genes & Cancer 4, 82-90
   Abstract »    Full Text »    PDF »
The Roles of SIRT1 in Cancer.
Z. Lin and D. Fang (2013)
Genes & Cancer 4, 97-104
   Abstract »    Full Text »    PDF »
SIRT1 is a Highly Networked Protein That Mediates the Adaptation to Chronic Physiological Stress.
M. W. McBurney, K. V. Clark-Knowles, A. Z. Caron, and D. A. Gray (2013)
Genes & Cancer 4, 125-134
   Abstract »    Full Text »    PDF »
Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury.
P.-H. Lou, L. Zhang, E. Lucchinetti, M. Heck, A. Affolter, M. Gandhi, P. C. Kienesberger, M. Hersberger, A. S. Clanachan, and M. Zaugg (2013)
Cardiovasc Res 97, 251-261
   Abstract »    Full Text »    PDF »
Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression.
W. Luo, R. Chang, J. Zhong, A. Pandey, and G. L. Semenza (2012)
PNAS 109, E3367-E3376
   Abstract »    Full Text »    PDF »
The Acetylase/Deacetylase Couple CREB-binding Protein/Sirtuin 1 Controls Hypoxia-inducible Factor 2 Signaling.
R. Chen, M. Xu, R. T. Hogg, J. Li, B. Little, R. D. Gerard, and J. A. Garcia (2012)
J. Biol. Chem. 287, 30800-30811
   Abstract »    Full Text »    PDF »
SIRT1 Negatively Regulates the Activities, Functions, and Protein Levels of hMOF and TIP60.
L. Peng, H. Ling, Z. Yuan, B. Fang, G. Bloom, K. Fukasawa, J. Koomen, J. Chen, W. S. Lane, and E. Seto (2012)
Mol. Cell. Biol. 32, 2823-2836
   Abstract »    Full Text »    PDF »
Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2.
N. R. Prabhakar and G. L. Semenza (2012)
Physiol Rev 92, 967-1003
   Abstract »    Full Text »    PDF »
Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism.
R. Nogueiras, K. M. Habegger, N. Chaudhary, B. Finan, A. S. Banks, M. O. Dietrich, T. L. Horvath, D. A. Sinclair, P. T. Pfluger, and M. H. Tschop (2012)
Physiol Rev 92, 1479-1514
   Abstract »    Full Text »    PDF »
HIF2{alpha}-Sp1 interaction mediates a deacetylation-dependent FVII-gene activation under hypoxic conditions in ovarian cancer cells.
S. Koizume, S. Ito, E. Miyagi, F. Hirahara, Y. Nakamura, Y. Sakuma, H. Osaka, Y. Takano, W. Ruf, and Y. Miyagi (2012)
Nucleic Acids Res. 40, 5389-5401
   Abstract »    Full Text »    PDF »
Evaluation of Sirtuin Role in Neuroprotection of Retinal Ganglion Cells in Hypoxia.
S. Balaiya, L. R. Ferguson, and K. V. Chalam (2012)
Invest. Ophthalmol. Vis. Sci. 53, 4315-4322
   Abstract »    Full Text »    PDF »
SIRT1 deacetylates SATB1 to facilitate MARHS2-MAR{varepsilon} interaction and promote {varepsilon}-globin expression.
Z. Xue, X. Lv, W. Song, X. Wang, G.-N. Zhao, W.-T. Wang, J. Xiong, B.-B. Mao, W. Yu, B. Yang, et al. (2012)
Nucleic Acids Res. 40, 4804-4815
   Abstract »    Full Text »    PDF »
The updated biology of hypoxia-inducible factor.
S. N. Greer, J. L. Metcalf, Y. Wang, and M. Ohh (2012)
EMBO J. 31, 2448-2460
   Abstract »    Full Text »    PDF »
FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging.
M. F. Oellerich and M. Potente (2012)
Circ. Res. 110, 1238-1251
   Abstract »    Full Text »    PDF »
Hepatic Deletion of SIRT1 Decreases Hepatocyte Nuclear Factor 1{alpha}/Farnesoid X Receptor Signaling and Induces Formation of Cholesterol Gallstones in Mice.
A. Purushotham, Q. Xu, J. Lu, J. F. Foley, X. Yan, D.-H. Kim, J. K. Kemper, and X. Li (2012)
Mol. Cell. Biol. 32, 1226-1236
   Abstract »    Full Text »    PDF »
Four-and-a-Half LIM Domain Proteins Inhibit Transactivation by Hypoxia-inducible Factor 1.
M. E. Hubbi, D. M. Gilkes, J. H. Baek, and G. L. Semenza (2012)
J. Biol. Chem. 287, 6139-6149
   Abstract »    Full Text »    PDF »
SIRT1 is dispensable for function of hematopoietic stem cells in adult mice.
V. Leko, B. Varnum-Finney, H. Li, Y. Gu, D. Flowers, C. Nourigat, I. D. Bernstein, and A. Bedalov (2012)
Blood 119, 1856-1860
   Abstract »    Full Text »    PDF »
Hypoxia-Induced Angiogenesis: Good and Evil.
B. L. Krock, N. Skuli, and M. C. Simon (2011)
Genes & Cancer 2, 1117-1133
   Abstract »    Full Text »    PDF »
Sirtuin 1 (SIRT1): The Misunderstood HDAC.
W. Stunkel and R. M. Campbell (2011)
J Biomol Screen 16, 1153-1169
   Abstract »    Full Text »    PDF »
Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart.
M. N. Sack (2011)
Am J Physiol Heart Circ Physiol 301, H2191-H2197
   Abstract »    Full Text »    PDF »
SIRT1 Is Essential for Oncogenic Signaling by Estrogen/Estrogen Receptor {alpha} in Breast Cancer.
S. Elangovan, S. Ramachandran, N. Venkatesan, S. Ananth, J. P. Gnana-Prakasam, P. M. Martin, D. D. Browning, P. V. Schoenlein, P. D. Prasad, V. Ganapathy, et al. (2011)
Cancer Res. 71, 6654-6664
   Abstract »    Full Text »    PDF »
Hypoxia-induced methylation of a pontin chromatin remodeling factor.
J. S. Lee, Y. Kim, J. Bhin, H.-J. R. Shin, H. J. Nam, S. H. Lee, J.-B. Yoon, O. Binda, O. Gozani, D. Hwang, et al. (2011)
PNAS 108, 13510-13515
   Abstract »    Full Text »    PDF »
HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells.
J. Mathieu, Z. Zhang, W. Zhou, A. J. Wang, J. M. Heddleston, C. M. A. Pinna, A. Hubaud, B. Stadler, M. Choi, M. Bar, et al. (2011)
Cancer Res. 71, 4640-4652
   Abstract »    Full Text »    PDF »
SIRT6 Promotes DNA Repair Under Stress by Activating PARP1.
Z. Mao, C. Hine, X. Tian, M. Van Meter, M. Au, A. Vaidya, A. Seluanov, and V. Gorbunova (2011)
Science 332, 1443-1446
   Abstract »    Full Text »    PDF »
Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B.
C. L. Partch and K. H. Gardner (2011)
PNAS 108, 7739-7744
   Abstract »    Full Text »    PDF »
Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner.
R. Chen, E. M. Dioum, R. T. Hogg, R. D. Gerard, and J. A. Garcia (2011)
J. Biol. Chem. 286, 13869-13878
   Abstract »    Full Text »    PDF »
Sirtuins at a glance.
T. Nakagawa and L. Guarente (2011)
J. Cell Sci. 124, 833-838
   Full Text »    PDF »
Regulation of erythropoietin production.
W. Jelkmann (2011)
J. Physiol. 589, 1251-1258
   Abstract »    Full Text »    PDF »
Lysine deacetylation in ischaemic preconditioning: the role of SIRT1.
S. M. Nadtochiy, E. Redman, I. Rahman, and P. S. Brookes (2011)
Cardiovasc Res 89, 643-649
   Abstract »    Full Text »    PDF »
SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse.
X. Ou, H.-D. Chae, R.-H. Wang, W. C. Shelley, S. Cooper, T. Taylor, Y.-J. Kim, C.-X. Deng, M. C. Yoder, and H. E. Broxmeyer (2011)
Blood 117, 440-450
   Abstract »    Full Text »    PDF »
Hexosamines stimulate apoptosis by altering SIRT1 action and levels in rodent pancreatic {beta}-cells.
M. Lafontaine-Lacasse, G. Dore, and F. Picard (2011)
J. Endocrinol. 208, 41-49
   Abstract »    Full Text »    PDF »
Pregnancy and interferon {tau} regulate DDX58 and PLSCR1 in the ovine uterus during the peri-implantation period.
G. Song, J.-A. G. W. Fleming, J. Kim, T. E. Spencer, and F. W. Bazer (2011)
Reproduction 141, 127-138
   Abstract »    Full Text »    PDF »
PGC-1{alpha} regulates a HIF2{alpha}-dependent switch in skeletal muscle fiber types.
K. A. Rasbach, R. K. Gupta, J. L. Ruas, J. Wu, E. Naseri, J. L. Estall, and B. M. Spiegelman (2010)
PNAS 107, 21866-21871
   Abstract »    Full Text »    PDF »
Sirtuins and Their Relevance to the Kidney.
C.-M. Hao and V. H. Haase (2010)
J. Am. Soc. Nephrol. 21, 1620-1627
   Abstract »    Full Text »    PDF »
Hypoxic regulation of erythropoiesis and iron metabolism.
V. H. Haase (2010)
Am J Physiol Renal Physiol 299, F1-F13
   Abstract »    Full Text »    PDF »
Shear stress, SIRT1, and vascular homeostasis.
Z. Chen, I.-C. Peng, X. Cui, Y.-S. Li, S. Chien, and J. Y.-J. Shyy (2010)
PNAS 107, 10268-10273
   Abstract »    Full Text »    PDF »
DYRK1A and DYRK3 Promote Cell Survival through Phosphorylation and Activation of SIRT1.
X. Guo, J. G. Williams, T. T. Schug, and X. Li (2010)
J. Biol. Chem. 285, 13223-13232
   Abstract »    Full Text »    PDF »
Aiming Straight for the Heart: Prolyl Hydroxylases Set the BAR.
J. A. Garcia (2009)
Science Signaling 2, pe70
   Abstract »    Full Text »    PDF »
The Emerging Characterization of Lysine Residue Deacetylation on the Modulation of Mitochondrial Function and Cardiovascular Biology.
Z. Lu, I. Scott, B. R. Webster, and M. N. Sack (2009)
Circ. Res. 105, 830-841
   Abstract »    Full Text »    PDF »
Hypoxic Hookup.
L. Guarente (2009)
Science 324, 1281-1282
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882