Enigmatic MYC Conducts an Unfolding Systems Biology Symphony

Abstract

The enigmatic MYC oncogene, which participates broadly in cancers, revealed itself recently as the maestro of an unfolding symphony of cell growth, proliferation, death, and metabolism. The study of MYC is arguably most challenging to its students but at the same time exhilarating when MYC reveals its deeply held secrets. It is the excitement of our richer understanding of MYC that is captured in each review of this special issue of Genes & Cancer. Collectively, our deeper understanding of MYC reveals that it is a symphony conductor, controlling a large orchestra of target genes. Although MYC controls many orchestra sections, which are necessary but not sufficient for Myc function, ribosome biogenesis stands out to reveal Myc's primordial function particularly in fruit flies. Because ribosome biogenesis and the associated translational machinery are bioenergetically demanding, Myc's other target genes involved in energy metabolism must be coupled with energy demand to ensure that cells can replicate their genome and produce daughter cells. Normal cells have feedback loops that diminish MYC expression when nutrients are scarce. On the other hand, when deregulated Myc transforms cells, their constitutive bioenergetic demand can trigger cell death when energy is unavailable. This special issue captures the unfolding symphony of MYC-mediated tumorigenesis through reviews that span from a timeline of MYC research, fundamental understanding of how the MYC gene itself is regulated, the study of Myc in model organisms, Myc function, and target genes to translational research in search of new therapeutic modalities for the treatment of cancer.

Figure 1.

The MYC gene is depicted downstream of different signal transduction pathways, such as WNT, Notch, receptor tyrosine kinases (RTK), and TGFβ. The MYC gene produces the Myc transcription factor, which dimerizes with Max, recruits TFIIH, and stimulates RNA polymerase activity to activate target genes. Myc affects diverse types of target genes regulated by RNA polymerases I, II, and III as illustrated.

Figure 2.

Schema of receptor signaling through cytoplasmic integrators such as mTORC1, mTORC2, and AKT or other relays that stimulate MYC expression. The cytoplasmic integrators through posttranscriptional modification of substrate proteins or Myc via activation of target genes can stimulate a cellular response that increases the uptake of energy and anabolic building blocks to support translation for cell growth and proliferation.

Figure 3.

Conceptual normal and cancer cell networks are depicted as starburst nodes linked by edges (lines). (A) The normal cell has a maintenance resting cell network, composed of key housekeeping subnetworks (purple and black starbursts), and is depicted to acquire an increase in the Myc network of genes with growth factor signaling. Myc further induces the energy metabolic network of genes to support the concurrent activation of genes involved in ribosome biogenesis (Ribi), a metabolically demanding node. Once committed into cycle, the cell replicates and divides into daughter cells. (B) Example of a deregulated Myc-driven cancer cell network, in which the Myc network of target genes is deregulated constitutively. The Myc-driven cancer cell is depicted with decreased dependency on growth factors and constitutive activation of Ribi genes concurrently with genes stimulating cellular uptake of energy and anabolic building blocks. When energy supply is sufficient, the cancer cells continue to divide. In energy-limiting conditions, metabolic demand outstrips energy availability, culminating in asynchrony and cell death.