Control of nucleotide biosynthesis by the MYC oncoprotein

The MYC oncoprotein drives cell cycle progression in both normal cells and human tumors. In fact, MYC overexpression provides such a proliferative advantage that a remarkable percentage of human tumors exhibit elevated MYC levels.¹ Hyper-proliferation requires that cells ramp up biosynthetic pathways for protein and lipid production, energy metabolism and DNA replication. Evidence for MYC controlling multiple points in the pathways leading to protein synthesis and energy metabolism has come from a variety of sources in recent years.² The study by Mannava published in this issue, along with similar findings from the Dang group, now firmly links MYC to the production of nucleotides required as building blocks for DNA synthesis. After finding that human melanoma cell lines required MYC for optimal proliferation, Mannava et al. identified MYC target genes that might explain this requirement by using expression profiling. Among the targets they identified were genes encoding enzymes that regulate several rate-limiting steps in nucleotide biosynthesis. At least three of these enzymes, thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2), are encoded by direct MYC target genes. As predicted by this set of observations, MYC depletion resulted in decreased cellular dNTP levels. Using the gold standard for epistatis experiments, Mannava ultimately show that ectopic expression of TS, IMPDH2 and PRPS2 partially rescues the proliferative defect caused by MYC depletion in melanoma cells.

These observations are strengthened by the independent findings of the Dang group. Dang et al. also identified IMPDH2 (and IMPDH1) as a MYC target using an unbiased screen for MYC binding sites in the genome.³ These studies were conducted in different cell types than the melanomas used by Manneva et al. suggesting that the link between MYC and nucleotide biosynthesis holds true across very distinct lineages. More broadly, the Dang group, unlike Manneva et al. found that genes involved in nucleotide metabolism were statistically overrepresented among their list of MYC targets.

These two exciting studies appear against the backdrop of previous work linking MYC to this pathway. A number of years ago, similar excitement was generated by evidence that MYC controlled transcription of CAD,⁴ the gene encoding the first three enzymes required for pyrimidine biosynthesis. While CAD is clearly regulated by MYC in many settings, subsequent studies showed that its levels were not linked to MYC in Burkitt’s lymphoma.⁵ Thus, these new studies linking MYC to nucleotide biosynthesis renew optimism that we might now have the mechanistic explanation for how MYC provides one of the essential sets of building blocks necessary as it pushes cell proliferation.

Relevant to these findings, a study from the Dalla-Favera group last year showed a role for MYC in the function of origins of DNA replication.⁶ Coupled with a role for MYC in generating the nucleotides necessary for DNA synthesis, this finding implicates MYC in controlling multiple nodes in the pathway leading to genome duplication. This seems to be MYC’s favorite modus operandi, as it often regulates critical pathways by regulating a number of important steps.

The true litmus test for the importance of these findings will be when studies are conducted examining levels of these proteins in more human tumor types driven by MYC overexpression (eg. Burkitt’s lymphoma, breast cancer, colon cancer).

Certainly drugs like mycophenolic acid, which inhibit nucleotide biosynthesis, have been effective chemotherapeutics for cancer and other hyper-proliferative diseases,⁷ and the Dang group show that mycophenolic acid treatment blocks MYC induced proliferation.³ In the clinic, drugs blocking this pathway in transplant recipients in order to squelch the immune response, led to an unanticipated decrease in cancer incidence.⁸

While it is not surprising that depleting nucleotide pools blocks proliferation, knowing specific enzymatic steps that are regulated by MYC may allow for more selective therapy. Since MYC appears to transform cells by exacting modest increases in a wide number of pathways, studies like those described here provide a critical knowledge base that will ultimately inform the design of combination therapy to simultaneously inhibit multiple MYC-regulated pathways.