Regulation of cancer cell metabolism: oncogenic MYC in the driver's seat

Abstract

Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. As such, most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming. Transcription factors of the MYC family are deregulated in up to 70% of all human cancers through a variety of mechanisms. Oncogenic levels of MYC regulates almost every aspect of cellular metabolism, a recently revisited hallmark of cancer development. Meanwhile, unrestrained growth in response to oncogenic MYC expression creates dependency on MYC-driven metabolic pathways, which in principle provides novel targets for development of effective cancer therapeutics. In the current review, we summarize the significant progress made toward understanding how MYC deregulation fuels metabolic rewiring in malignant transformation.

Fig. 1

MYC coordinates global metabolic reprogramming. Deregulation of MYC frequently occurs in human cancers through a variety of mechanisms, such as chromosome amplification/translocation, super-enhancer activation, and aberrant upstream signaling. MYC deregulation rewires multiple metabolic pathways to generate energy, building blocks, and reducing power for growing tumor cells. EAA essential amino acid

Fig. 2

MYC regulation of glucose, glutamine, and proline metabolism. MYC promotes glucose metabolism by upregulating glucose transporters and nearly all the glycolytic enzymes. MYC ellicts glutamine addiction by promoting glutamine uptake and glutaminolysis. MYC promotes proline anabolism and represses its catabolism. Enzymes labeled in red are upregulated by MYC, and those labeled in green are suppressed by MYC. α-KG α-ketoglutarate, ALDOA aldolase A, 1,3BPG 1,3-bisphosphoglycerate, Cit citrate, ENO enolase, F1,6-BP fructose 1,6-bisphosphate, F6P fructose 6-phosphate, GA3P glyceraldehyde-3-phosphate, GAPDH glyceraldehyde-3-phosphate dehydrogenase, Gln glutamine, GLS glutaminase, Glu glutamate, GOT2 glutamate oxaloacetate transaminase, G6P glucose-6-phosphate, GPI phosphoglucose isomerase, GPT glutamine pyruvate transaminase, GS glutamine synthetase, GSA glutamic-γ-semialdehyde, HK hexokinase, LDHA lactate dehydrogenase A, Mal malate, MCT monocarboxylate transporter, P5C Δ¹-pyyroline-5-carboxylate, P5CDH P5C dehydrogenase, P5CS P5C synthase, PDH pyruvate dehydrogenase, PEP phosphoenolpyruvate, PFK phosphofructokinase, PG phosphoglycerate, PGK phosphoglycerate kinase, PGM phosphoglucomutase, PKM2 pyruvate kinase M2, POX/PRODH proline oxidase/dehydrogenase, Pro proline, PYCR P5C reductase, Pyr pyruvate, SLC solute carrier family, Suc succinate, TCA tricarboxylic acid

Fig. 3

MYC regulation of essential amino acid and lipid metabolism. MYC activates critical transporters, SLC7A5, SLC43A1, and SLC1A5, to promote essential amino acid transport. BCAT1, which catalyzes the decomposition of branched amino acids, is a downstream target of MYC. MYC promotes tryptophan uptake and metabolism by the kynurenine pathway. MYC coordinates glucose, glutamine, and essential amino acid metabolism to promote fatty acid biosynthesis. Enzymes labeled in red are upregulated by MYC. ACC acetyl-coA carboxylase, ACLY ATP citrate lyase, AFMID arylformamidase, BCAA branched-chain amino acid BCAT branched-chain aminotransferase, BCKA branched-chain α-keto acid, FA fatty acid, FASN fatty acid synthase, Fum fumarate, His histidine, HMG-CoA 3-hydroxy-3-methylglutaryl-CoA, HMGCR 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, Ile isoleucine, KMO kynurenine-3-monooxygenase, Kyn kynurenine, KYNU kynureninase, Leu leucine, Met methionine, OAA oxaloacetate, Phe phenylalanine, SCD stearoyl-CoA desaturase, Thr threonine, Trp tryptophan, Val valine

Fig. 4

MYC coordinates multiple metabolic events to activate nucleotide metabolism. MYC activates ODC, SMS, and SRM to promote polyamine biosynthesis. MYC drives nucleotide biosynthesis (1) by facilitating generation of PRPP, which offers skeleton for de novo purine and pyrimidine biosynthesis; (2) by facilitating generation of serine and glycine, which offers one-carbon unit for folate cycle; and (3) by directly inducing enzymes involved in de novo nucleotide biosynthesis. Enzymes labeled in red are upregulated by MYC. ARG1 arginase 1, AMP adenosine monophosphate, CAD carbamoyl-phosphate synthetase; CDP cytosine diphosphate; CHOTHF formyl tetrahydrofolate; CH2THF 5,10-methylene tetrahydrofolate; CH3THF methyl tetrahydrofolate, CTP cytosine triphosphate, dcSAM decarboxylated S-adenosyl-methionine, DHO dihydroorotate, DHODH dihydroorotate dehydrogenase, DHF dihydrofolate, dUDP deoxyuridine diphosphate, dTMP deoxythymidine monophosphate, Gly glycine, GMPS guanosine monophosphate synthetase, G6PD glucose-6-phosphate dehydrogenase, IMP inosine monophosphate, IMPDH inosine-5′-monophosphate dehydrogenase, MTA 5′-methylthioadenosine, MTR 5-methylthioribose-1-phosphate, ODC ornithine decarboxylase, OMP orotate monophosphate, PHGDH phosphoglycerate dehydrogenase, PPAT phosphoribosyl pyrophosphate amidotransferase, PPP pentose phosphate pathway, PRA 5-phosphoribosylamine, PRPP phosphoribosyl pyrophosphate, PRPS pyrophosphate synthetase, PSAT phosphoserine aminotransferase, PSPH phosphate ester hydrolysis, PUT putrescine, R5P ribose 5-phosphate, SAM S-adenosyl methionine, Ser serine, SHMT serine hydroxymethyltransferase, SMS spermine synthase, SPD spermidine, SPM spermine, SRM spermidine synthase, THF tetrahydrofolate, Tkt transketolase, TS thymidylate synthase, UDP uridine diphosphate, UTP uridine triphosphate

Fig. 5

Metabolic regulation of MYC expression and transcriptional activity. Expression of MYC is downstream of multiple control mechanisms, as shown in a–d, which are regulated by nutrient levels and respond to metabolic stress. See text for more details. AMPK AMP-activated protein kinase, B55α also termed Ppp2r2a, a specific B subunit of PP2A, EDD E3 identified by differential display, eIF eukaryotic initiation factor, FOXOs forkhead transcription factors of the O class, GCN2 general control non-derepressible-2, OGT O-linked N-acetylglucosamine transferase, PI3K phosphatidylinositol 3-kinase, S6K1 effector S6 kinase 1, URI unconventional prefoldin RPB5 interactor