Interactions between Myc and MondoA transcription factors in metabolism and tumourigenesis

Abstract

Metabolic reprogramming towards aerobic glycolysis is a common feature of transformed cells and can be driven by a network of transcription factors. It is well established that c-Myc and hypoxia-inducible factor-1α (HIF-1α) contribute to metabolic reprogramming by driving the expression of glycolytic target genes. More recently, the c-Myc-related transcription factor MondoA has been shown to restrict glucose uptake and aerobic glycolysis via its induction of thioredoxin-interacting protein (TXNIP). Three recent studies demonstrate that complex and cancer type-specific interactions between c-Myc, MondoA and HIF-1α underlie metabolism, tumourigenesis and drug response. In triple-negative breast cancer, c-Myc blocks MondoA-dependent activation of TXNIP to stimulate aerobic glycolysis. In contrast, in neuroblastoma, N-Myc requires MondoA for metabolic reprogramming and tumourigenesis. Finally, the therapeutic response of BRAF(V600E) melanoma cells to vemurafenib requires downregulation of c-Myc and HIF-1α and upregulation of MondoA-TXNIP, and the subsequent reprogramming away from aerobic glycolysis. In this minireview we highlight the findings in these three studies and present a working model to explain why c-Myc and MondoA function cooperatively in some cancers and antagonistically in others.

Figure 1

The extended Myc network. Transcriptional activation and repression mediated by Myc/Max and Max/Mxd respectively drive a transcriptional profile that coordinates nutrient utilisation. Transcriptional activation and repression by Mondo/Mlx make up a nutrient sensing branch of the network.

Figure 2

Myc and MondoA coordinate nutrient utilisation. In triple-negative breast cancer and melanoma, Myc and MondoA competitively influence glucose metabolism, whereas in neuroblastoma and possibly B-ALL, MondoA and Myc cooperatively drive glutamine metabolism and lipogenesis.