MYC on the path to cancer

Abstract

The MYC oncogene contributes to the genesis of many human cancers. Recent insights into its expression and function have led to therapeutic opportunities. MYC's activation by bromodomain proteins could be inhibited by drug-like molecules, resulting in tumor inhibition in vivo. Tumor growth can also be curbed by pharmacologically uncoupling bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced cellular biomass accumulation. Other approaches to halt Myc on the path to cancer involve targeting Myc-Max dimerization or Myc-induced microRNA expression. Here the richness of our understanding of MYC is reviewed, highlighting new biological insights and opportunities for cancer therapies.

Figure 1

A. The MYC protooncogene is depicted downstream of receptor signal transduction pathways, which elicit positive or negative regulation of the MYC gene. MYC produces the transcription factor Myc, which dimerizes with Max and bind target DNA sequences or E-boxes (with the sequence 5′-CANNTG-3′) to regulate transcription of genes involved in cell growth and proliferation. The WNT pathway is depicted with APC negatively regulating β-catenin, which upon nuclear translocation participates in the transactivation of MYC, such that loss of APC results in constitutive oncogenic MYC expression. B. When MYC is deregulated, by gene amplication, chromosomal translocation or loss of upstream regulators, such as APC, acute sustained oncogenic MYC expression results in checkpoint activation p53 or Arf. Loss of checkpoint regulation through mutations of p53 or Arf, for example, uncloaks MYC’s full tumorigenic potential.

Figure 1

A. The MYC protooncogene is depicted downstream of receptor signal transduction pathways, which elicit positive or negative regulation of the MYC gene. MYC produces the transcription factor Myc, which dimerizes with Max and bind target DNA sequences or E-boxes (with the sequence 5′-CANNTG-3′) to regulate transcription of genes involved in cell growth and proliferation. The WNT pathway is depicted with APC negatively regulating β-catenin, which upon nuclear translocation participates in the transactivation of MYC, such that loss of APC results in constitutive oncogenic MYC expression. B. When MYC is deregulated, by gene amplication, chromosomal translocation or loss of upstream regulators, such as APC, acute sustained oncogenic MYC expression results in checkpoint activation p53 or Arf. Loss of checkpoint regulation through mutations of p53 or Arf, for example, uncloaks MYC’s full tumorigenic potential.

Figure 2

A. The Myc-Max heterodimer is shown to interact with key co-factors such as TFIIH that triggers transcriptional elongation or TRRAP that recruits the GCN5, which acetylates histone, permitting transcription of target genes. B. Myc-Max also mediates gene repression. Miz-1 is shown tethered to the INR element to regulate transcription of target genes, which could be silenced by Myc displacement of NPM, a Miz-1 cofactor, or by Myc induction of the ribosomal protein RPL23, which retains NPM in the nucleolus, keeping it away from Miz-1.

Figure 3

Myc regulates a network of microRNAs through activation of the miR-17-92 cluster and repression of dozens of miRs including Let-7, which was recently shown to affect insulin signaling, miR-23a/b, which regulates glutaminase expression, and miR-34a, which was shown to regulate lactate dehydrogenase (LDHA) expression. The miR-17 cluster contains microRNAs that targets PTEN, thereby activating AKT, and those that targets the proapoptotic BimL or the transcription factor E2F1 expression. MicroRNAs downstream of Myc have also been implicated in epithelial-mesenchymal transition and angiogenesis.

Figure 4

Myc-Max is shown bound to E-box driven genes, which could also be regulated by other E-box transcription factors, such as the carbohydrate response element binding protein (ChREBP), sterol response element binding protein (SREBP), nuclear respiratory factor 1 (NRF1), circadian transcription factor Clock (and Bmal), and hypoxia inducible factor (HIF). The non-Myc E-box transcription factors regulate genes involved in metabolism, which is maintained for cellular homeostasis when cells are not proliferating. Upon activation of MYC and elevated levels of Myc, mass action favors the binding of Myc-Max to E-box genes to regulate metabolism and genes involved in ribosomal biogenesis and cell mass accumulation. This model suggests that resting cells express metabolic genes through ‘homeostatic’ E-box transcription factors, which regulate a set of genes that overlaps with Myc target genes that are expressed when cells are stimulate to grow and proliferate.