Lipid Metabolic Reprogramming in Embryonal Neoplasms with MYCN Amplification

Abstract

Tumor cells reprogram their metabolism, including glucose, glutamine, nucleotide, lipid, and amino acids to meet their enhanced energy demands, redox balance, and requirement of biosynthetic substrates for uncontrolled cell proliferation. Altered lipid metabolism in cancer provides lipids for rapid membrane biogenesis, generates the energy required for unrestricted cell proliferation, and some of the lipids act as signaling pathway mediators. In this review, we focus on the role of lipid metabolism in embryonal neoplasms with MYCN dysregulation. We specifically review lipid metabolic reactions in neuroblastoma, retinoblastoma, medulloblastoma, Wilms tumor, and rhabdomyosarcoma and the possibility of targeting lipid metabolism. Additionally, the regulation of lipid metabolism by the MYCN oncogene is discussed.

Keywords: MYCN; cancer; embryonal tumors; lipid metabolism; therapeutic targeting.

Figure 2

The fundamental biosynthetic pathways of lipid metabolism in cancer [46,77,78]. The red color indicates the important enzymes involved in lipid metabolism. The blue color indicates the key lipid metabolic pathways. ACSS1/2—acyl-coenzyme A synthetase short-chain family member 1/2; ACSL—long chain acyl CoA synthase; ACAT2—acetyl CoA acetyl transferase 2; AGPAT2—1-acylglycerol-3-phosphate O-acyl transferase 2; ACC-A/B—acetyl CoA carboxylase A/B; CPT1/2—carnitine palmitoyl transferase 1/2; CD36—cluster of differentiation 36; DGAT—diglyceride acyltransferase; ELOVL—elongation of very long chain fatty acids; FASN—fatty acid synthase complex; FADS1/2—fatty acid desaturase 1/2; FATP—fatty acid transport protein; GPAT—glycerol-3-phosphate acyl transferase; HMGCR—3-hydroxy-3-methylglutaryl CoA reductase; HMGCS1—3-hydroxy-3-methylglutaryl CoA synthase 1; LPIN—lipin; LDL—low-density lipoprotein; LDLR—low-density lipoprotein receptor; PDHC—pyruvate dehydrogenase complex; SCD—stearoyl-CoA desaturase. A few of the icons were used from Biorender.com (accessed on 16 March 2023).

Figure 1

(A) MYCN structure. Blue boxes represent the conserved MYC homology boxes; yellow box represents nuclear localization signal (NLS); red box represents the basic Helix-Loop-Helix-Leucine Zipper (bHLH-LZ) domain. AA: amino acid. (B) Functions of MYCN in cancers [16,35,36].

Figure 3

Gene expression profile of lipid metabolic enzymes in Neuroblastoma. The median expression of various lipid metabolic enzymes found in neuroblastoma was retrieved from Human Protein Atlas [150,151]. nTPM—number of transcripts per million; nTPM > 1 is considered to be a cancer-specific enhanced expression in multiple cell lines. ACSS1/2—acyl CoA synthetase short-chain family member 1/2; ACSL—long chain acyl CoA synthases; ACAT2—acetyl CoA acetyl transferase 2; ACC-A/B—acetyl CoA carboxylase A/B; CPT1/2—carnitine palmitoyl transferase 1/2; DGAT—diglyceride acyltransferase; ELOVL—elongation of very long chain fatty acids; FASN—fatty acid synthase complex; FADS—fatty acid desaturase; HMGCS—3-hydroxy-3-methylglutaryl CoA synthase; LPIN—lipin; SCD—stearoyl CoA desaturase; SREBF—sterol regulatory element binding factor; EHHADH—enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase; PLA2G15—phospholipase A2 Group XV; ACAD—acyl-CoA dehydrogenase short-chain; LIPG—lipase G; SOAT1—sterol O-acyltransferase 1.

Figure 4

Possible regulation of key lipid metabolic enzymes by MYCN. The promoter sequence of important lipid metabolic enzymes was analyzed for the presence of MYC-binding E-boxes. The few key enzymes possibly regulated by MYCN are shown. MYCN—MYC- neuroblastoma derived; MAX—MYC associated factor X; FASN—fatty acid synthase; FADS1/2—fatty acid desaturase 1/2; CPT1—carnitine palmitoyl transferase 1; SCD1—stearoyl-CoA desaturase 1; ELOVL5—elongation of very long chain fatty acids 5. DNA double-strand icon was taken from Biorender.com (accessed on 16 March 2023).

Figure 5

The location of MYCN binding E-box motifs on the promoter region of lipid metabolic enzymes. FASN—fatty acid synthase; FADS1—fatty acid desaturase 1; CPT1—carnitine palmitoyl transferase 1; ACAT2—acetyl CoA acetyltransferase; ACC-A—acetyl CoA carboxylase—A; SCD1—stearoyl-CoA desaturase 1; SREBF—sterol regulatory element binding factor; ELOVL5—elongation of very long chain fatty acids 5.