MYC and metabolism on the path to cancer

Abstract

The MYC proto-oncogene is frequently deregulated in human cancers, activating genetic programs that orchestrate biological processes to promote growth and proliferation. Altered metabolism characterized by heightened nutrients uptake, enhanced glycolysis and glutaminolysis and elevated fatty acid and nucleotide synthesis is the hallmark of MYC-driven cancer. Recent evidence strongly suggests that Myc-dependent metabolic reprogramming is critical for tumorigenesis, which could be attenuated by targeting specific metabolic pathways using small drug-like molecules. Understanding the complexity of MYC-mediated metabolic re-wiring in cancers as well as how MYC cooperates with other metabolic drivers such as mammalian target of rapamycin (mTOR) will provide translational opportunities for cancer therapy.

Keywords: Cancer; Metabolism; Myc; mTOR.

Fig. 1

Expression of metabolic genes bound by both Bmal1 and Myc in different stages of Myc-driven liver tumor in mice. Gene set enrichment analysis of a subset of metabolic genes bound by both Bmal1 and Myc (shown in Table 1) in four stages of liver tumors in liver specific, doxycycline-suppressed, Myc transgenic mice: control (+DOX), pre-tumor (−DOX), tumor (−DOX), tumor regression (+DOX). DOX, doxycycline; red, upregulation; blue, downregulation.

Fig. 2

Hypothesis of Myc-disrupted circadian homeostasis. A schematic representation of rhythmic control of “E-box” containing metabolic genes in normal cells and Myc-dependent, sustained control of “E-box” containing metabolic genes in cancer cells.

Fig. 3

Growth factor signaling pathway. Upon growth factor engaging to growth factor receptor, receptor tyrosine kinase (RTK) activates both PI3K-AKT-mTOR pathway and RAS-RAF-MEK-ERK pathway. Myc is activated downstream of ERK. Oncogenes are framed with green burst and tumor suppressor genes are framed with red octagon. Both pathways collectively drive synthesis of macromolecules and bioenergetics molecules to promote cell growth and proliferation.

Fig. 4

Schematic of divergent effects of mTOR and Myc on growing cells. In a hypothetical cell containing only mTOR downstream of growth factor signaling (upper row), mTOR enhances the rate of translation (ribosomes labeled in red representing they are undergoing faster translation process, so called “speedy” ribosomes) through posttranslational regulation. However, since there is no new components of translational machinery were made, the growth promoting effect is short-lived. In most mammalian cells (lower row), growth factor signaling activates both mTOR and Myc, in addition to elevated mTOR-dependent protein translation, Myc induces transcriptions of components of translational machinery to further enhance and sustain growth.

Fig. 5

Myc-driven metabolic network. A schematic representation of the metabolic pathways regulated by Myc. Metabolic enzymes (except for eIF4E, which is eukaryotic translation initiation factor) labeled in red representing enzymes encoded by Myc direct target genes. Myc drives glucose metabolism by upregulating glucose transporter (GLUT1), glycolysis genes hexokinase (HK), phosphofructokinase (PFK3), pyruvate kinase (PKM) and lactate dehydrogenase (LDH). Myc also upregulates pyruvate dehydrogenase kinase (PDK) to inhibit pyruvate dehydrogenase, which further enhances the conversion of pyruvate to lactate. Myc upregulates phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase (SHMT) to increase serine and glycine metabolism. Myc promotes glutamine metabolism by upregulating glutamine transporter (ASCT2) and glutaminase (GLS). Fatty acid synthesis is often prominent in Myc-driven cancer cells. Global mapping of Myc target genes shows acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1) are directly regulated by Myc [76].