SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization

被引：716

作者：

Finley, Lydia W. S. ^{[1
]}

Carracedo, Arkaitz ^{[2
,3
,4
]}

Lee, Jaewon ^{[1
]}

Souza, Amanda ^{[5
]}

Egia, Ainara ^{[2
,3
]}

Zhang, Jiangwen ^{[6
]}

Teruya-Feldstein, Julie ^{[7
]}

Moreira, Paula I. ^{[8
]}

Cardoso, Sandra M. ^{[8
]}

Clish, Clary B. ^{[5
]}

Pandolfi, Pier Paolo ^{[2
,3
]}

Haigis, Marcia C. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA

[2] Harvard Univ, Beth Israel Deaconess Med Ctr, Beth Israel Deaconess Canc Ctr, Canc Genet Program,Med Sch,Dept Med, Boston, MA 02215 USA

[3] Harvard Univ, Beth Israel Deaconess Med Ctr, Beth Israel Deaconess Canc Ctr, Canc Genet Program,Med Sch,Dept Pathol, Boston, MA 02215 USA

[4] CIC bioGUNE, Derio 48160, Spain

[5] Broad Inst MIT & Harvard, Metabolite Profiling Initiat, Cambridge, MA 02142 USA

[6] Harvard Univ, Ctr Syst Biol, Fac Arts & Sci, Cambridge, MA 02138 USA

[7] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Pathol, New York, NY 10065 USA

[8] Univ Coimbra, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal

来源：

CANCER CELL | 2011年 / 19卷 / 03期

基金：

美国国家科学基金会;

关键词：

BROWN ADIPOSE-TISSUE; OXIDATIVE STRESS; TUMOR-SUPPRESSOR; BREAST-CANCER; HYPOXIA; HIF-1-ALPHA; ACTIVATION; TRANSFORMATION; TRANSCRIPTION; MITOCHONDRIA;

D O I：

10.1016/j.ccr.2011.02.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondria! NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1 alpha (HIF1 alpha), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1 alpha stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1 alpha target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.

引用

页码：416 / 428

页数：13

共 43 条

[1] A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis [J].

Ahn, Bong-Hyun ;

Kim, Hyun-Seok ;

Song, Shiwei ;

Lee, In Hye ;

Liu, Jie ;

Vassilopoulos, Athanassios ;

Deng, Chu-Xia ;

Finkel, Toren .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (38) :14447-14452

[2] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[3] Hypoxia signalling controls metabolic demand [J].

Brahimi-Horn, M. Christiane ;

Chiche, Johanna ;

Pouyssegur, Jacques .

CURRENT OPINION IN CELL BIOLOGY, 2007, 19 (02) :223-229

[4] Brown adipose tissue: Function and physiological significance [J].

Cannon, B ;

Nedergaard, J .

PHYSIOLOGICAL REVIEWS, 2004, 84 (01) :277-359

[5] Mitochondrial reactive oxygen species trigger hypoxia-induced transcription [J].

Chandel, NS ;

Maltepe, E ;

Goldwasser, E ;

Mathieu, CE ;

Simon, MC ;

Schumacker, PT .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (20) :11715-11720

[6] High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer [J].

Chin, Suet F. ;

Teschendorff, Andrew E. ;

Marioni, John C. ;

Wang, Yanzhong ;

Barbosa-Morais, Nuno L. ;

Thorne, Natalie P. ;

Costa, Jose L. ;

Pinder, Sarah E. ;

van de Wiel, Mark A. ;

Green, Andrew R. ;

Ellis, Ian O. ;

Porter, Peggy L. ;

Tavare, Simon ;

Brenton, James D. ;

Ylstra, Bauke ;

Caldas, Carlos .

GENOME BIOLOGY, 2007, 8 (10)

[7] The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth [J].

Christofk, Heather R. ;

Vander Heiden, Matthew G. ;

Harris, Marian H. ;

Ramanathan, Arvind ;

Gerszten, Robert E. ;

Wei, Ru ;

Fleming, Mark D. ;

Schreiber, Stuart L. ;

Cantley, Lewis C. .

NATURE, 2008, 452 (7184) :230-U74

[8] Regulation of Succinate Dehydrogenase Activity by SIRT3 in Mammalian Mitochondria [J].

Cimen, Huseyin ;

Han, Min-Joon ;

Yang, Yongjie ;

Tong, Qiang ;

Koc, Hasan ;

Koc, Emine C. .

BIOCHEMISTRY, 2010, 49 (02) :304-311

[9]

CLAVO AC, 1995, J NUCL MED, V36, P1625

[10] Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1 [J].

Duevel, Katrin ;

Yecies, Jessica L. ;

Menon, Suchithra ;

Raman, Pichai ;

Lipovsky, Alex I. ;

Souza, Amanda L. ;

Triantafellow, Ellen ;

Ma, Qicheng ;

Gorski, Regina ;

Cleaver, Stephen ;

Heiden, Matthew G. Vander ;

MacKeigan, Jeffrey P. ;

Finan, Peter M. ;

Clish, Clary B. ;

Murphy, Leon O. ;

Manning, Brendan D. .

MOLECULAR CELL, 2010, 39 (02) :171-183

← 1 2 3 4 5 →