Deletion of Gene Enhancer DNA Improves Cancer Resistance in Mice with No Apparent Loss of Normal Tissue Function

The path to effective control of cancer involves finding common mechanisms that target many different types of cancer, departing from the present approach of one costly project for every subtype of cancer. Here, researchers undertake a novel approach to the challenge, finding a sizable region of the genome that can be deleted in mice with no apparent loss of normal function. The deletion improves cancer resistance to a degree that makes suppression of the contents of this region of the genome worth pursuing as the basis for therapies that might control many types of cancer.

Our cells each contain close to 20,000 genes, which provide the instructions needed to build our bodies and keep us alive. At any one time in the life of the cell, only some of these genes are active. The activity of each gene is constantly regulated to allow the cell to respond to changes in its environment. Enhancers are sections of DNA, outside of the genes, that act as molecular switches controlling the activity of genes. A gene can have many such enhancers; each enhancer is linked to a particular set of signals and having multiple enhancers allows the same gene to be activated by different signals in different tissues in the body.

Changes to enhancers can have serious consequences. By altering the activity of genes, an enhancer can have widespread effects on the health and behavior of a cell, including transforming it from healthy to cancerous. The small differences in enhancers also make some people more susceptible to cancers than others. If we can identify enhancers whose activity is commonly altered in cancers, it could be possible to target them through treatment. Yet, it is not clear whether targeting enhancers in this way could be effectively used to treat cancer without damaging healthy cells.

Now, researchers have examined a large enhancer region with known links to several different cancers - including prostate, breast and colon cancers - to uncover whether it also plays a critical role in healthy cells and if it could be safely targeted for treatment. The region has multiple enhancers for a cancer-linked gene called MYC and is implicated in many cancer-associated deaths every year. This particular enhancer region is found in both humans and mice, which share many genes in common. Using genetic engineering, researchers removed this enhancer region from the genetic information of a group of mice. The experiment showed that mice without the enhancer region were completely healthy. Also, when tested for cancer development, these mice were much less susceptible to several major types of cancer.

The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kilobase deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer therapy.



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