title: Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming.
abstract: In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.
authors.affiliation: Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Bernadette M M
authors.initials: BM
authors.lastname: Zwaans
authors.affiliation: Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA davidlom@umich.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
mesh_terms: D049109:Cell Proliferation; D016259:Genes, myc; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D037761:Sirtuins / Q000502:physiology*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D016271:Proto-Oncogene Proteins c-myc; D037761:Sirtuins
keywords: HIF; MYC; Metabolic reprogramming; Sirtuins; Warburg effect
references.citation: Nat Cell Biol. 2012 Nov;14(11):1203-11
references.pmid: 23041974
references.citation: Cell. 2012 Sep 28;151(1):68-79
references.pmid: 23021216
references.citation: J Biol Chem. 1997 Mar 28;272(13):8581-93
references.pmid: 9079689
references.citation: Nature. 2012 Feb 22;483(7388):218-21
references.pmid: 22367546
references.citation: Clin Cancer Res. 2009 Nov 1;15(21):6479-83
references.pmid: 19861459
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715-20
references.pmid: 9751731
references.citation: Mol Cell. 2014 Feb 20;53(4):534-48
references.pmid: 24486017
references.citation: DNA Cell Biol. 2012 May;31(5):745-52
references.pmid: 22149724
references.citation: Mech Dev. 1997 Apr;63(1):51-60
references.pmid: 9178256
references.citation: Cell Rep. 2013 Dec 26;5(6):1639-49
references.pmid: 24332849
references.citation: Sci Rep. 2013 Oct 30;3:3085
references.pmid: 24169447
references.citation: Cancer Res. 2007 Feb 1;67(3):854-5
references.pmid: 17283112
references.citation: J Biol Chem. 2005 Jun 3;280(22):21313-20
references.pmid: 15795229
references.citation: Cell Metab. 2014 Apr 1;19(4):605-17
references.pmid: 24703693
references.citation: Protein Cell. 2013 Sep;4(9):702-10
references.pmid: 23982738
references.citation: Mol Cell Proteomics. 2011 Dec;10(12):M111.012658
references.pmid: 21908771
references.citation: J Biol Chem. 2011 Apr 22;286(16):14575-87
references.pmid: 21362626
references.citation: Mol Med Rep. 2014 Mar;9(3):882-8
references.pmid: 24366394
references.citation: Nature. 2012 Jul 5;487(7405):114-8
references.pmid: 22722849
references.citation: Cell Cycle. 2012 Apr 1;11(7):1445-54
references.pmid: 22395432
references.citation: Science. 2011 Nov 11;334(6057):806-9
references.pmid: 22076378
references.citation: Nature. 2011 Nov 20;481(7381):380-4
references.pmid: 22101433
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
references.pmid: 7539918
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4273-8
references.pmid: 9113979
references.citation: Nature. 2013 Apr 11;496(7444):238-42
references.pmid: 23535595
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21790-4
references.pmid: 21098266
references.citation: Science. 1955 Sep 16;122(3168):501-14
references.pmid: 13255879
references.citation: Cancer Cell. 2012 Mar 20;21(3):297-308
references.pmid: 22439925
references.citation: Carcinogenesis. 2013 Jul;34(7):1476-86
references.pmid: 23514751
references.citation: Nature. 2011 Sep 21;477(7365):E1-2
references.pmid: 21938026
references.citation: Nat Rev Cancer. 2011 Dec 15;12(1):9-22
references.pmid: 22169972
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
references.pmid: 18032601
references.citation: Nat Rev Cancer. 2008 Jan;8(1):51-6
references.pmid: 18046334
references.citation: Cell Death Differ. 2013 Mar;20(3):503-14
references.pmid: 23175188
references.citation: J Cell Biol. 2007 Jul 2;178(1):93-105
references.pmid: 17606868
references.citation: Oncogene. 2011 Jun 30;30(26):2986-96
references.pmid: 21358671
references.citation: Trends Genet. 2014 Jul;30(7):271-86
references.pmid: 24877878
references.citation: Cell. 2009 Jan 9;136(1):62-74
references.pmid: 19135889
references.citation: Anticancer Drugs. 2013 Sep;24(8):862-70
references.pmid: 23797802
references.citation: Biochem Biophys Res Commun. 1999 Jun 24;260(1):273-9
references.pmid: 10381378
references.citation: Genome Res. 2012 Oct;22(10):1963-73
references.pmid: 22955140
references.citation: Cancer Biol Ther. 2005 Nov;4(11):1285-94
references.pmid: 16319523
references.citation: Nature. 2012 Mar 07;483(7388):166-7
references.pmid: 22367538
references.citation: Eur J Hum Genet. 2013 Dec;21(12):1369-76
references.pmid: 23612572
references.citation: Cancer Cell. 2007 Aug;12(2):108-13
references.pmid: 17692803
references.citation: Cardiovasc Res. 2013 Mar 1;97(3):391-2
references.pmid: 23257021
references.citation: Cancer Res. 2011 Nov 15;71(22):6921-5
references.pmid: 22084445
references.citation: Cancer Cell. 2010 Jan 19;17(1):41-52
references.pmid: 20129246
references.citation: Cell. 2006 Jul 28;126(2):257-68
references.pmid: 16873059
references.citation: FASEB J. 2003 Feb;17(2):271-3
references.pmid: 12490539
references.citation: Cancer Cell. 2011 Mar 8;19(3):416-28
references.pmid: 21397863
references.citation: Blood. 2009 Jul 9;114(2):469-77
references.pmid: 19439736
references.citation: Br J Pharmacol. 2013 Jan;168(1):117-28
references.pmid: 22335191
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11800-5
references.pmid: 22753495
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Nature. 2008 Dec 18;456(7224):971-5
references.pmid: 19011615
references.citation: PLoS One. 2012;7(3):e33433
references.pmid: 22479397
references.citation: Genes Dev. 2000 Jun 1;14(11):1390-9
references.pmid: 10837031
references.citation: Nat Med. 2012 Nov;18(11):1643-50
references.pmid: 23086477
references.citation: Tumour Biol. 2013 Jun;34(3):1847-54
references.pmid: 23475622
references.citation: Cell. 2012 Sep 28;151(1):56-67
references.pmid: 23021215
references.citation: J Biol Chem. 2013 Oct 25;288(43):31350-6
references.pmid: 24052263
references.citation: Cancer Sci. 2013 Mar;104(3):275-81
references.pmid: 23279446
references.citation: J Biol Chem. 2012 Nov 30;287(49):40924-37
references.pmid: 23086953
references.citation: Cell. 2010 Nov 24;143(5):802-12
references.pmid: 21094524
references.citation: Mol Cell Proteomics. 2014 Jan;13(1):168-83
references.pmid: 24163442
references.citation: Cell. 2012 Dec 7;151(6):1185-99
references.pmid: 23217706
references.citation: Mediators Inflamm. 2012;2012:597514
references.pmid: 23132960
references.citation: Acta Biochim Biophys Sin (Shanghai). 2013 Jan;45(1):18-26
references.pmid: 23257292
references.citation: Curr Opin Genet Dev. 2010 Feb;20(1):51-6
references.pmid: 19942427
references.citation: J Biol Chem. 2007 Nov 16;282(46):33583-33592
references.pmid: 17715127
references.citation: Curr Opin Genet Dev. 2010 Feb;20(1):87-90
references.pmid: 20006486
references.citation: Cancer Cell. 2011 Oct 18;20(4):487-99
references.pmid: 22014574
references.citation: Trends Biochem Sci. 2010 Aug;35(8):427-33
references.pmid: 20570523
references.citation: Cell Cycle. 2010 May 15;9(10):1960-71
references.pmid: 20495363
references.citation: PLoS One. 2012;7(9):e45119
references.pmid: 23024800
references.citation: Nature. 2008 Mar 27;452(7186):492-6
references.pmid: 18337721
references.citation: Mol Cell. 2013 Jun 27;50(6):919-30
references.pmid: 23806337
references.citation: J Cell Sci. 2013 Nov 15;126(Pt 22):5166-77
references.pmid: 24013546
references.citation: Cell Metab. 2010 Dec 1;12(6):662-7
references.pmid: 21109198
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
references.pmid: 19033189
references.citation: Biochem Pharmacol. 2013 Sep 15;86(6):726-33
references.pmid: 23856293
references.citation: Cell Metab. 2013 Sep 3;18(3):416-30
references.pmid: 24011076
references.citation: Int J Biochem Cell Biol. 2011 Nov;43(11):1573-81
references.pmid: 21807113
references.citation: Science. 2010 Sep 10;329(5997):1348-53
references.pmid: 20829486
references.citation: Cardiovasc Res. 2013 Mar 1;97(3):571-9
references.pmid: 23201774
references.citation: Cell. 2012 Mar 30;149(1):22-35
references.pmid: 22464321
references.citation: Aging (Albany NY). 2010 Apr;2(4):185-99
references.pmid: 20442453
references.citation: Nature. 2011 Sep 21;477(7365):482-5
references.pmid: 21938067
references.citation: Oncotarget. 2012 Oct;3(10):1182-93
references.pmid: 23045412
references.citation: Mol Cell Biol. 2003 Dec;23(24):9361-74
references.pmid: 14645546
references.citation: Nature. 2011 Nov 20;481(7381):385-8
references.pmid: 22101431
references.citation: J Biol Chem. 2013 Jul 19;288(29):20768-20775
references.pmid: 23750001
references.citation: Cell Cycle. 2009 Aug 15;8(16):2662-3
references.pmid: 19597350
references.citation: Ann N Y Acad Sci. 2006 May;1067:182-90
references.pmid: 16803984
references.citation: PLoS Genet. 2011 Jun;7(6):e1002135
references.pmid: 21698133
references.citation: Aging (Albany NY). 2009 Jan 15;1(1):109-21
references.pmid: 20157594
references.citation: Oncogene. 1990 Dec;5(12):1787-97
references.pmid: 2284098
references.citation: Cell. 2004 Sep 17;118(6):781-94
references.pmid: 15369676
references.citation: J Cell Biol. 2009 Apr 20;185(2):203-11
references.pmid: 19364925
references.citation: Cancer Cell. 2013 Apr 15;23(4):450-63
references.pmid: 23562301
references.citation: Cell. 2013 Jul 18;154(2):430-41
references.pmid: 23870130
references.citation: Nature. 2013 Apr 4;496(7443):110-3
references.pmid: 23552949
references.citation: Cancer Res. 2010 Feb 1;70(3):859-62
references.pmid: 20086171
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):829-33
references.pmid: 17213307
references.citation: J Biol Chem. 2010 Nov 19;285(47):36776-84
references.pmid: 20847051
references.citation: Mol Cell. 2013 Aug 22;51(4):454-68
references.pmid: 23911928
references.citation: Free Radic Biol Med. 2013 Mar;56:133-71
references.pmid: 23104101
references.citation: Nat Commun. 2010 Apr 12;1:3
references.pmid: 20975665
references.citation: Mol Cell Biol. 2005 Jul;25(13):5675-86
references.pmid: 15964822
references.citation: Science. 2009 Jun 5;324(5932):1289-93
references.pmid: 19498162
references.citation: Cell Metab. 2010 Sep 8;12(3):224-36
references.pmid: 20816089
references.citation: Aging Cell. 2010 Apr;9(2):162-73
references.pmid: 20047575
references.citation: Cancer Discov. 2011 Oct;1(5):442-56
references.pmid: 22059152
references.citation: Cell. 2013 May 9;153(4):840-54
references.pmid: 23663782
references.citation: J Lipid Res. 2013 Oct;54(10):2745-53
references.pmid: 23881913
references.citation: Cell Cycle. 2011 Sep 15;10(18):3153-8
references.pmid: 21900744
references.citation: Aging (Albany NY). 2013 Apr;5(4):315-27
references.pmid: 23765091
references.citation: Cell Metab. 2012 Jan 4;15(1):4-5
references.pmid: 22225869
references.citation: Mol Cell. 2012 Dec 28;48(6):900-13
references.pmid: 23142079
references.citation: Cell. 2004 Jan 23;116(2):235-46
references.pmid: 14744434
references.citation: J Biol Chem. 2014 Feb 14;289(7):4135-44
references.pmid: 24368766
references.citation: J Biol Chem. 2012 Dec 7;287(50):41903-13
references.pmid: 23076146
references.citation: Cell. 2006 Sep 8;126(5):941-54
references.pmid: 16959573
references.citation: Cell Rep. 2013 Nov 14;5(3):654-665
references.pmid: 24210820
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):E187-96
references.pmid: 22190494
references.citation: Hepatology. 2013 Sep;58(3):1054-64
references.pmid: 23526469
references.citation: Mol Cell. 2010 Jun 25;38(6):864-78
references.pmid: 20620956
references.citation: Nature. 2009 Apr 9;458(7239):762-5
references.pmid: 19219026
references.citation: Cell. 2010 Jan 22;140(2):280-93
references.pmid: 20141841
references.citation: Genes Dev. 2009 Mar 1;23(5):537-48
references.pmid: 19270154
references.citation: Cell Rep. 2013 Sep 12;4(5):905-12
references.pmid: 24012758
references.citation: Arthritis Rheum. 2013 Jul;65(7):1776-85
references.pmid: 23553536
references.citation: Cell. 2006 Jan 27;124(2):315-29
references.pmid: 16439206
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10684-9
references.pmid: 25009184
references.citation: Genes Dev. 1997 Jan 1;11(1):72-82
references.pmid: 9000051
references.citation: Cell Cycle. 2009 Aug 15;8(16):2664-6
references.pmid: 19625767
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683
references.citation: Cancer Cell. 2007 Apr;11(4):335-47
references.pmid: 17418410