MYC and the art of microRNA maintenance

Abstract

MYC is a noncanonical transcription factor that binds to thousands of genomic loci and affects >15% of the human transcriptome, with surprisingly little overlap between MYC-bound and -regulated genes. This discordance raises the question whether MYC chooses its targets based on their individual biological effects ("a la carte") or by virtue of belonging to a certain group of genes (on a "prix fixe" basis). This review presents evidence for a prix fixe, posttranscriptional model whereby MYC initially deregulates a select number of microRNAs. These microRNAs then target a broad spectrum of genes based solely on the presence in their 3' UTRs (untranslated regions) of distinct "seed" sequences. Existing evidence suggests that there are significant microRNA components to all key MYC-driven phenotypes, including cell-cycle progression, apoptosis, metabolism, angiogenesis, metastasis, stemness, and hematopoiesis. Furthermore, each of these cell-intrinsic and -extrinsic phenotypes is likely attributable to deregulation of multiple microRNA targets acting in different, yet frequently overlapping, pathways. The habitual targeting of multiple genes within the same pathway might account for the robustness and persistence of MYC-induced phenotypes.

Figure 1.

Gene regulation by MYC: a la carte or prix fixe? (A) Comparison of MYC-bound versus MYC-regulated genes in P493-6 cells. (B) Model of MYC-mediated gene regulation through the microRNA pathway. (C) The miR-17–92 cluster, which accounts for most posttranscriptional MYC targets.

Figure 2.

MYC-regulated microRNAs and their cell-cycle-related targets. The MYC-stimulated cyclin D1/2/3 (green), cyclin E1/2 (orange), and CDK-4/-6 (purple), and the MYC-repressed p21 (red) are shown. E2F (pink) is both MYC-stimulated and -repressed. Each stage of the cell cycle regulated by these targets is represented and the coordinated regulation of these targets promotes cell-cycle progression.

Figure 3.

MYC-regulated microRNAs and apoptosis. Relevant MYC-repressed (green) and -stimulated (purple) targets are shown. The coordinated regulation of these targets inhibits apoptosis.

Figure 4.

MYC-regulated microRNAs and metabolic alterations. Relevant MYC-repressed (green) and -stimulated (purple) targets are shown. Important metabolic processes (blue) are depicted. The coordinated regulation of these targets promotes aerobic glycolysis and uses glutamine for the tricarboxylic acid cycle (TCA) cycle.

Figure 5.

MYC-regulated microRNAs during angiogenesis and metastasis. Relevant MYC-repressed (green) and -stimulated (purple) targets are shown. The EMT (blue) promotes metastasis. The coordinated regulation of these targets promotes angiogenesis and metastasis.

Figure 6.

MYC-regulated microRNAs in stem cells. Relevant MYC-repressed (green) and -stimulated (purple) targets are shown. Important processes in stem cell biology (blue) are depicted. The coordinated regulation of these targets promotes stem-cell-like properties.

Figure 7.

MYC-regulated microRNAs in normal and malignant hematopoiesis. Relevant MYC-repressed (green) and -stimulated (purple) targets are shown. Important processes in hematopoiesis (blue) are depicted.