New Cancer Treatments Would Block Genes Required by the Myc Oncogene

A paper described a novel strategy for killing cancer cells that depend on the activity of the Myc oncogene for their propensity for uncontrolled growth.

Myc is a very strong protooncogene, and it is very often found to be upregulated in many types of cancers. The Myc protein encoded by this gene is a transcription factor that activates expression of a great number of genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 coactivator, it inhibits expression of Miz-1 target genes. Myc is activated upon various mitogenic signals such as Wnt, Shh, and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The protein encoded by Myc has been found to be highly resistant to chemotherapy mainly because it lacks efficient binding sites for drug compounds.

In the current study investigators at Harvard Medical School (Boston, MA, USA) and their colleagues at the Baylor College of Medicine (Houston, TX, USA) based a high-throughput screen of more than 75,000 short-hairpin RNAs (shRNAs) on the principle of “synthetic lethality,” or the cell-killing effect of having two incompatible mutations in a shared pathway. By stimulating Myc activity and then screening for genes that caused cell death, they were able to identify 403 genes that were required by Myc. Of particular interest was the SUMO-activating enzyme (SAE1/2).

The investigators reported in the December 8, 2011, online edition of the journal Science that SAE2 was required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggested that low SAE1/SAE2 levels in the tumors correlated with longer metastasis-free survival of the patients. At the cellular level, Myc-activated cells in which SAE2 was depleted were unable to build normal mitotic spindles and were unable to divide correctly. Thus, SAE2 depletion blocked Myc's ability to activate genes involved in spindle formation.

Commenting on the 403 Myc-associated genes, contributing author Dr. Stephen Elledge, professor of genetics at Harvard Medical School, said, “These genes are not oncogenes in and of themselves, but they do code for proteins that Myc relies on to cause cancer. We see them as potential targets for drug therapy--even if you cannot target Myc, you can target these other genes and inactivate its effects. We would also like to delve more into the mechanism. We would like to know more specifically which proteins Myc depends on--if we can hit those targets with drugs, we might be able to turn Myc off and kill cancer cells selectively.”

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Harvard Medical School
Baylor College of Medicine