Abstract
The MYC oncogene plays a pivotal role in the development and progression of human cancers. It encodes a transcription factor that has broad reaching effects on many cellular functions, most importantly in driving cell growth through regulation of genes involved in ribosome biogenesis, metabolism, and cell cycle. Upon binding DNA with its partner MAX, MYC recruits factors that release paused RNA polymerases to drive transcription and amplify gene expression. At physiologic levels of MYC, occupancy of high-affinity DNA-binding sites drives ‘house-keeping’ metabolic genes and those involved in ribosome and mitochondrial biogenesis for biomass accumulation. At high oncogenic levels of MYC, invasion of low-affinity sites and enhancer sequences alter the transcriptome and cause metabolic imbalances, which activates stress response and checkpoints such as p53. Loss of checkpoints unleashes MYC’s full oncogenic potential to couple metabolism with neoplastic cell growth and division. Cells that overexpress MYC, however, are vulnerable to metabolic perturbations that provide potential new avenues for cancer therapy.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aguda BD, Kim Y, Piper-Hunter MG, Friedman A, Marsh CB (2008) MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci USA 105(50):19678–19683. doi:10.1073/pnas.0811166106
Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8(6):450–461. doi:10.1038/nrg2102
Altman BJ, Hsieh AL, Sengupta A, Krishnanaiah SY, Stine ZE, Walton ZE, Gouw AM, Venkataraman A, Li B, Goraksha-Hicks P, Diskin SJ, Bellovin DI, Simon MC, Rathmell JC, Lazar MA, Maris JM, Felsher DW, Hogenesch JB, Weljie AM, Dang CV (2015) MYC disrupts the circadian clock and metabolism in cancer cells. Cell Metab. doi:10.1016/j.cmet.2015.09.003
Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G (2014) Serine and glycine metabolism in cancer. Trends Biochem Sci 39(4):191–198. doi:10.1016/j.tibs.2014.02.004
Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, Rao PH, Ruggero D (2008) Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456(7224):971–975. doi:10.1038/nature07449
Ben-Sahra I, Howell JJ, Asara JM, Manning BD (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339(6125):1323–1328. doi:10.1126/science.1228792
Berkers CR, Maddocks OD, Cheung EC, Mor I, Vousden KH (2013) Metabolic regulation by p53 family members. Cell Metab 18(5):617–633. doi:10.1016/j.cmet.2013.06.019
Blackwell TK, Huang J, Ma A, Kretzner L, Alt FW, Eisenman RN, Weintraub H (1993) Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol 13(9):5216–5224
Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, Cheng PF, Anderson S, Ulrich M, Hurley JB, Raftery D, Ayer DE, Eisenman RN (2015) Deregulated Myc requires mondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 27(2):271–285. doi:10.1016/j.ccell.2014.11.024
Cermelli S, Jang IS, Bernard B, Grandori C (2014) Synthetic lethal screens as a means to understand and treat MYC-driven cancers. Cold Spring Harbor Perspect Med 4(3). doi:10.1101/cshperspect.a014209
Chayka O, D’Acunto CW, Middleton O, Arab M, Sala A (2015) Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells. J Biol Chem 290(4):2198–2212. doi:10.1074/jbc.M114.624056
Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133(6):1106–1117. doi:10.1016/j.cell.2008.04.043
Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C (2013) Emerging landscape of oncogenic signatures across human cancers. Nat Genet 45(10):1127–1133. doi:10.1038/ng.2762
Coller HA, Grandori C, Tamayo P, Colbert T, Lander ES, Eisenman RN, Golub TR (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci USA 97(7):3260–3265
Cunningham JT, Moreno MV, Lodi A, Ronen SM, Ruggero D (2014) Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157(5):1088–1103. doi:10.1016/j.cell.2014.03.052
Dai MS, Lu H (2004) Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J Biol Chem 279(43):44475–44482. doi:10.1074/jbc.M403722200
Dang CV (2012a) Links between metabolism and cancer. Genes Dev 26(9):877–890. doi:10.1101/gad.189365.112
Dang CV (2012b) MYC on the path to cancer. Cell 149(1):22–35. doi:10.1016/j.cell.2012.03.003
Dang CV (2013) MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med 3 (8). doi:10.1101/cshperspect.a014217
Dang CV, Kim JW, Gao P, Yustein J (2008) The interplay between MYC and HIF in cancer. Nat Rev Cancer 8(1):51–56. doi:10.1038/nrc2274
den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A, Kremer M, Graf N, Scheerer M, Hall MA, Goga A, von Bubnoff N, Duyster J, Peschel C, Cleveland JL, Nilsson JA, Keller U (2010) Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116(9):1498–1505. doi:10.1182/blood-2009-11-251074
Doherty JR, Yang C, Scott KE, Cameron MD, Fallahi M, Li W, Hall MA, Amelio AL, Mishra JK, Li F, Tortosa M, Genau HM, Rounbehler RJ, Lu Y, Dang CV, Kumar KG, Butler AA, Bannister TD, Hooper AT, Unsal-Kacmaz K, Roush WR, Cleveland JL (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74(3):908–920. doi:10.1158/0008-5472.CAN-13-2034
Eberlin LS, Gabay M, Fan AC, Gouw AM, Tibshirani RJ, Felsher DW, Zare RN (2014) Alteration of the lipid profile in lymphomas induced by MYC overexpression. Proc Natl Acad Sci USA 111(29):10450–10455. doi:10.1073/pnas.1409778111
Efeyan A, Zoncu R, Sabatini DM (2012) Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med 18(9):524–533. doi:10.1016/j.molmed.2012.05.007
Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL (1999) Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13(20):2658–2669
Elkon R, Zeller KI, Linhart C, Dang CV, Shamir R, Shiloh Y (2004) In silico identification of transcriptional regulators associated with c-Myc. Nucleic Acids Res 32(17):4955–4961. doi:10.1093/nar/gkh816
Farrell PJ, Allan GJ, Shanahan F, Vousden KH, Crook T (1991) p53 is frequently mutated in Burkitt’s lymphoma cell lines. The EMBO journal 10(10):2879–2887
Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B (2003) Genomic targets of the human c-Myc protein. Genes Dev 17(9):1115–1129. doi:10.1101/gad.1067003
Fernandez-Sanchez ME, Gonatopoulos-Pournatzis T, Preston G, Lawlor MA, Cowling VH (2009) S-adenosyl homocysteine hydrolase is required for Myc-induced mRNA cap methylation, protein synthesis, and cell proliferation. Mol Cell Biol 29(23):6182–6191. doi:10.1128/MCB.00973-09
Gallant P, Shiio Y, Cheng PF, Parkhurst SM, Eisenman RN (1996) Myc and Max homologs in Drosophila. Science 274(5292):1523–1527
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765. doi:10.1038/nature07823
Gomez-Roman N, Grandori C, Eisenman RN, White RJ (2003) Direct activation of RNA polymerase III transcription by c-Myc. Nature 421(6920):290–294. doi:10.1038/nature01327
Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN, White RJ (2005) c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 7(3):311–318. doi:10.1038/ncb1224
Gregory MA, Qi Y, Hann SR (2003) Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem 278(51):51606–51612. doi:10.1074/jbc.M310722200
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395. doi:10.1038/nature08221
Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, Koumenis C (2012) ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Investig 122(12):4621–4634. doi:10.1172/JCI62973
Hatanaka M, Maier B, Sims EK, Templin AT, Kulkarni RN, Evans-Molina C, Mirmira RG (2014) Palmitate induces mRNA translation and increases ER protein load in islet beta-cells via activation of the mammalian target of rapamycin pathway. Diabetes 63(10):3404–3415. doi:10.2337/db14-0105
Hein N, Hannan KM, George AJ, Sanij E, Hannan RD (2013) The nucleolus: an emerging target for cancer therapy. Trends Mol Med 19(11):643–654. doi:10.1016/j.molmed.2013.07.005
Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, Hubbard GB, Ikeno Y, Zhang Y, Feng B, Li X, Serre T, Qi W, Van Remmen H, Miller RA, Bath KG, de Cabo R, Xu H, Neretti N, Sedivy JM (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell. doi:10.1016/j.cell.2014.12.016
Holland JP, Evans MJ, Rice SL, Wongvipat J, Sawyers CL, Lewis JS (2012) Annotating MYC status with 89Zr-transferrin imaging. Nat Med 18(10):1586–1591. doi:10.1038/nm.2935
Howell JJ, Manning BD (2011) mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol Metab TEM 22(3):94–102. doi:10.1016/j.tem.2010.12.003
Hung CL, Wang LY, Yu YL, Chen HW, Srivastava S, Petrovics G, Kung HJ (2014) A long noncoding RNA connects c-Myc to tumor metabolism. Proc Natl Acad Sci USA 111(52):18697–18702. doi:10.1073/pnas.1415669112
Iyer NV, Leung SW, Semenza GL (1998) The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation. Genomics 52(2):159–165. doi:10.1006/geno.1998.5416
Ji H, Wu G, Zhan X, Nolan A, Koh C, De Marzo A, Doan HM, Fan J, Cheadle C, Fallahi M, Cleveland JL, Dang CV, Zeller KI (2011) Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation. PLoS ONE 6(10):e26057. doi:10.1371/journal.pone.0026057
Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P (1999) Drosophila myc regulates cellular growth during development. Cell 98(6):779–790
Jones RM, Branda J, Johnston KA, Polymenis M, Gadd M, Rustgi A, Callanan L, Schmidt EV (1996) An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol Cell Biol 16(9):4754–4764
Jorgensen P, Tyers M (2004) How cells coordinate growth and division. Curr Biol CB 14(23):R1014–R1027. doi:10.1016/j.cub.2004.11.027
Kim S, Li Q, Dang CV, Lee LA (2000) Induction of ribosomal genes and hepatocyte hypertrophy by adenovirus-mediated expression of c-Myc in vivo. Proc Natl Acad Sci USA 97(21):11198–11202. doi:10.1073/pnas.200372597
Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV (2004) Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 24(13):5923–5936. doi:10.1128/MCB.24.13.5923-5936.2004
Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185. doi:10.1016/j.cmet.2006.02.002
Kim J, Roh M, Doubinskaia I, Algarroba GN, Eltoum IE, Abdulkadir SA (2012) A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. Oncogene 31(3):322–332. doi:10.1038/onc.2011.236
Koh CM, Bezzi M, Low DH, Ang WX, Teo SX, Gay FP, Al-Haddawi M, Tan SY, Osato M, Sabo A, Amati B, Wee KB, Guccione E (2015) MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature. doi:10.1038/nature14351
Kongsuwan K, Yu Q, Vincent A, Frisardi MC, Rosbash M, Lengyel JA, Merriam J (1985) A Drosophila Minute gene encodes a ribosomal protein. Nature 317(6037):555–558
Korangath P, Teo WW, Sadik H, Han L, Mori N, Huijts CM, Wildes F, Bharti S, Zhang Z, Santa-Maria CA, Tsai HL, Dang CV, Stearns V, Bhujwalla Z, Sukumar S (2015) Targeting glutamine metabolism in breast cancer with aminooxyacetate. Clin Cancer Res Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-1200
Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13(6):472–482. doi:10.1016/j.ccr.2008.05.005
Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 107(5):2037–2042. doi:10.1073/pnas.0914433107
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15(1):110–121. doi:10.1016/j.cmet.2011.12.009
Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25(14):6225–6234. doi:10.1128/MCB.25.14.6225-6234.2005
Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, Lee TI, Young RA (2012) Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151(1):56–67. doi:10.1016/j.cell.2012.08.026
Lippman SI, Broach JR (2009) Protein kinase A and TORC1 activate genes for ribosomal biogenesis by inactivating repressors encoded by Dot6 and its homolog Tod6. Proc Natl Acad Sci USA 106(47):19928–19933. doi:10.1073/pnas.0907027106
Liu YC, Li F, Handler J, Huang CR, Xiang Y, Neretti N, Sedivy JM, Zeller KI, Dang CV (2008) Global regulation of nucleotide biosynthetic genes by c-Myc. PLoS ONE 3(7):e2722. doi:10.1371/journal.pone.0002722
Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, Phang JM (2012) Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 109(23):8983–8988. doi:10.1073/pnas.1203244109
Lohrum MA, Ludwig RL, Kubbutat MH, Hanlon M, Vousden KH (2003) Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell 3(6):577–587
Mannava S, Grachtchouk V, Wheeler LJ, Im M, Zhuang D, Slavina EG, Mathews CK, Shewach DS, Nikiforov MA (2008) Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle 7(15):2392–2400
Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192. doi:10.1038/ncomms3192
Mayer C, Grummt I (2006) Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25(48):6384–6391. doi:10.1038/sj.onc.1209883
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773(8):1263–1284. doi:10.1016/j.bbamcr.2006.10.001
Miltenberger RJ, Sukow KA, Farnham PJ (1995) An E-box-mediated increase in cad transcription at the G1/S-phase boundary is suppressed by inhibitory c-Myc mutants. Mol Cell Biol 15(5):2527–2535
Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, Wang R, Green DR, Tessarollo L, Casellas R, Zhao K, Levens D (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151(1):68–79. doi:10.1016/j.cell.2012.08.033
O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843. doi:10.1038/nature03677
O’Donnell KA, Yu D, Zeller KI, Kim JW, Racke F, Thomas-Tikhonenko A, Dang CV (2006) Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol 26(6):2373–2386. doi:10.1128/MCB.26.6.2373-2386.2006
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275(29):21797–21800. doi:10.1074/jbc.C000023200
Pickering MT, Stadler BM, Kowalik TF (2009) miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene 28(1):140–145. doi:10.1038/onc.2008.372
Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, Sharp PA, Young RA (2010) c-Myc regulates transcriptional pause release. Cell 141(3):432–445. doi:10.1016/j.cell.2010.03.030
Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S, Prescianotto-Baschong C, Sauer U, Jenoe P, Hall MN (2013) Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339(6125):1320–1323. doi:10.1126/science.1228771
Sabo A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, Morelli MJ, Bora P, Doni M, Verrecchia A, Tonelli C, Faga G, Bianchi V, Ronchi A, Low D, Muller H, Guccione E, Campaner S, Amati B (2014) Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature. doi:10.1038/nature13537
Schreiber-Agus N, Stein D, Chen K, Goltz JS, Stevens L, DePinho RA (1997) Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Proc Natl Acad Sci USA 94(4):1235–1240
Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K, Johnson RS (2001) Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol 21(10):3436–3444. doi:10.1128/MCB.21.10.3436-3444.2001
Sears R, Ohtani K, Nevins JR (1997) Identification of positively and negatively acting elements regulating expression of the E2F2 gene in response to cell growth signals. Mol Cell Biol 17(9):5227–5235
Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271(51):32529–32537
Shim H, Chun YS, Lewis BC, Dang CV (1998) A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci USA 95(4):1511–1516
Shroff EH, Eberlin LS, Dang VM, Gouw AM, Gabay M, Adam SJ, Bellovin DI, Tran PT, Philbrick WM, Garcia-Ocana A, Casey SC, Li Y, Dang CV, Zare RN, Felsher DW (2015) MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci USA. doi:10.1073/pnas.1507228112
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig 118(12):3930–3942. doi:10.1172/JCI36843
Thai M, Graham NA, Braas D, Nehil M, Komisopoulou E, Kurdistani SK, McCormick F, Graeber TG, Christofk HR (2014) Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metab 19(4):694–701. doi:10.1016/j.cmet.2014.03.009
Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, Olejniczak ET, Clark T, Dey S, Lorey S, Alicie B, Howard GC, Cawthon B, Ess KC, Eischen CM, Zhao Z, Fesik SW, Tansey WP (2015) Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell 58(3):440–452. doi:10.1016/j.molcel.2015.02.028
Toyoshima M, Howie HL, Imakura M, Walsh RM, Annis JE, Chang AN, Frazier J, Chau BN, Loboda A, Linsley PS, Cleary MA, Park JR, Grandori C (2012) Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci USA 109(24):9545–9550. doi:10.1073/pnas.1121119109
van Riggelen J, Yetil A, Felsher DW (2010) MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer 10(4):301–309. doi:10.1038/nrc2819
Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wustefeld T, Fischer M, Teichmann M, Zender L, Wei CL, Sansom O, Wolf E, Eilers M (2014) Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature. doi:10.1038/nature13473
Warburg O (1956a) On the origin of cancer cells. Science 123(3191):309–314
Warburg O (1956b) On respiratory impairment in cancer cells. Science 124(3215):269–270
Williams KJ, Argus JP, Zhu Y, Wilks MQ, Marbois BN, York AG, Kidani Y, Pourzia AL, Akhavan D, Lisiero DN, Komisopoulou E, Henkin AH, Soto H, Chamberlain BT, Vergnes L, Jung ME, Torres JZ, Liau LM, Christofk HR, Prins RM, Mischel PS, Reue K, Graeber TG, Bensinger SJ (2013) An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res 73(9):2850–2862. doi:10.1158/0008-5472.CAN-13-0382-T
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105(48):18782–18787. doi:10.1073/pnas.0810199105
Wolf E, Lin CY, Eilers M, Levens DL (2014) Taming of the beast: shaping Myc-dependent amplification. Trends Cell Biol. doi:10.1016/j.tcb.2014.10.006
Wong JV, Yao G, Nevins JR, You L (2011) Viral-mediated noisy gene expression reveals biphasic E2f1 response to MYC. Mol Cell 41(3):275–285. doi:10.1016/j.molcel.2011.01.014
Xiang Y, Stine ZE, Xia J, Lu Y, O’Connor RS, Altman BJ, Hsieh AL, Gouw AM, Thomas AG, Gao P, Sun L, Song L, Yan B, Slusher BS, Zhuo J, Ooi LL, Lee CG, Mancuso A, McCallion AS, Le A, Milone MC, Rayport S, Felsher DW, Dang CV (2015) Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Investig. doi:10.1172/JCI75836
Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM (2010) Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci USA 107(31):13836–13841. doi:10.1073/pnas.1008366107
Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 178(1):93–105. doi:10.1083/jcb.200703099
Zeller KI, Zhao X, Lee CW, Chiu KP, Yao F, Yustein JT, Ooi HS, Orlov YL, Shahab A, Yong HC, Fu Y, Weng Z, Kuznetsov VA, Sung WK, Ruan Y, Dang CV, Wei CL (2006) Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci USA 103(47):17834–17839. doi:10.1073/pnas.0604129103
Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11(5):407–420. doi:10.1016/j.ccr.2007.04.001
Zirath H, Frenzel A, Oliynyk G, Segerstrom L, Westermark UK, Larsson K, Munksgaard Persson M, Hultenby K, Lehtio J, Einvik C, Pahlman S, Kogner P, Jakobsson PJ, Arsenian Henriksson M (2013) MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells. Proc Natl Acad Sci USA. doi:10.1073/pnas.1222404110
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Hsieh, A.L., Dang, C.V. (2016). MYC, Metabolic Synthetic Lethality, and Cancer. In: Cramer, T., A. Schmitt, C. (eds) Metabolism in Cancer. Recent Results in Cancer Research, vol 207. Springer, Cham. https://doi.org/10.1007/978-3-319-42118-6_4
Download citation
DOI: https://doi.org/10.1007/978-3-319-42118-6_4
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-42116-2
Online ISBN: 978-3-319-42118-6
eBook Packages: MedicineMedicine (R0)