Myc, Mondo, and Metabolism

Abstract

The Myc family of proto-oncogenes plays a central role in tumorigenesis, yet identifying the specific transcriptional targets required for its oncogenic function remains a challenge. Given Myc’s broad role in transcriptional regulation, it seems unlikely that there exists one or even a small set of Myc effectors strictly required for transformation. Over the last decade or so, it has become clear that Myc can drive several metabolic pathways associated with cell growth. There is compelling evidence that Myc regulates these pathways directly and that their regulation is not an epiphenomenon. As such, for understanding Myc’s pleiotropic role in cell growth, cell division, and cell death, it may be fruitful to focus more broadly on Myc-regulated pathways than on specific targets. Myc was first shown to regulate glycolysis, but it is now clear that Myc regulates many biosynthetic pathways required for cell growth and division. A related family of transcriptional regulators, the Mondo family, has recently been discovered that may interact with members of the Myc family to control cell growth. The Mondo family is a key sensor of intracellular bioenergetic charge, and one function appears to be in controlling the availability and utilization of intracellular glucose. Here we focus on the metabolic pathways regulated by Myc and Mondo and speculate on the largely unexplored question of their cooperation in controlling cancer cell metabolism.

Stress-induced cleavage of Myc promotes cancer cell survival

“…This is consistent with reports that tumor hypoxia is associated with poor clinical outcome (Hockel et al 1996;Jubb et al 2009). Many tumors exhibit deregulated Myc activity that augments growth and proliferation, which in turn requires increased amounts of carbon sources such as glucose and glutamine in order to meet the needs of reprogrammed anabolic metabolism (Dang 2010(Dang , 2012Sloan and Ayer 2010;Vander Heiden et al 2010). Indeed, withdrawal of glucose and glutamine from Myc transformed cells causes a dramatic induction of cell death in vitro (Shim et al 1998;Yuneva et al 2007).…”

An Overview of MYC and Its Interactome

“…MYC, complexed with MIZ-1, has been shown to repress MXD4 in erythroleukemia cells (Kime and Wright 2003). MYC also appears to up-regulate MondoA and ChREBP, factors that in turn influence MYCdriven metabolic reprogramming during tumor progression (Lin et al 2009;Kaadige et al 2010;Sloan and Ayer 2010;P Carroll, D Diolaiti, L McFerrin et al, unpubl.). Increased abundance of MondoA and ChREBP would be expected to sequester MLX, potentially blocking the formation of MXD -MLX dimers.…”

MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling

“…The known mechanisms of MondoA regulation are also consistent with this notion. For example, MondoA nuclear levels are increased by glucose metabolites, including phosphometabolites, which could serve as indicators of high glucose flux and ample energy phosphate stores (51,52). In addition, inhibition of oxidative phosphorylation results in deactivation of MondoA, which would release its inhibition on glucose import and fuel catabolic flux (53).…”