Study reveals how networks of switches in DNA, which regulate gene expression, drive cancer growth

Enhancers are pieces of DNA that act like switches, regulating when genes are turned on and off and how strongly they are activated. Scientists know these switches play a critical role in cancer and other diseases, but they have yet to fully understand how enhancers work together to control gene expression.

A new study, which focused on the DNA switches of prostate cancer cells, reveals new insights into enhancers that become active during cancer development and turn on genes linked to the disease. The study found that enhancers work cooperatively in 3D networks, rather than as isolated switches. Some enhancers function as “central hubs” that control many genes, while others play a supporting role. The findings, just published in Genome Biology, a Springer Nature journal, could help with the development of targeted cancer therapies.

“How enhancers interact with one another is critical. What we’ve shown for the first time is that there is a hierarchy of enhancers—some act as master switches, playing a central role in regulating many enhancers and genes, while others are more compensatory,” said the study’s corresponding author, Suhn Kyong Rhie, Ph.D., assistant professor of cancer biology at the Keck School of Medicine of USC and a member of the USC Norris Comprehensive Cancer Center.

The findings also add to scientists’ understanding of noncoding DNA, which does not direct the synthesis of proteins and makes up about 99% of the human genome. Once dismissed as “junk DNA,” these regions are now known to play a critical role in regulating gene activity.

Enhancers are already the target of one FDA-approved gene-editing therapy, Casgevy, which treats sickle cell disease and transfusion-dependent β-thalassemia by targeting an enhancer to alter gene expression. The new study, which was supported in part by the National Institutes of Health, could lay the foundation for a similar approach to treating prostate cancer or other diseases.

“We think these findings will apply to many other cells, tissues and diseases. At this point, it’s basic science that shows the complexity of how the genome works, but it also has the potential to inform future therapies,” Rhie said.

Mapping 3D enhancer networks in prostate cancer

Rhie’s lab focuses on chromatin interactions, a specialized area of research that investigates how DNA folds and interacts to regulate gene expression. Using 201 datasets from both prostate tumor samples and healthy prostate tissue, her team identified 3,216 key enhancers specific to prostate cancer.

They then zoomed in on one region of the genome and used an advanced technique known as Region Capture Micro-C to map physical interactions between enhancers and genes at extremely high resolution. They found that in prostate cancer cells, enhancers formed an interconnected 3D network that did not exist in normal prostate cells.

Next, they used the gene-editing tool CRISPR to delete enhancers one at a time and observe how this affected enhancer activity, chromatin interactions, gene expression and cancer cell growth.

They found that not all enhancers were equivalent. Deleting some enhancers had little effect. Deleting other “central” enhancers disrupted the entire network, reducing the activity of other enhancers, switching off many cancer-promoting genes and slowing cancer cell growth.

Targeting central enhancers for future therapies

The discovery that some enhancers serve as key control points could inform future cancer therapies. Rather than targeting individual genes, gene-editing therapies could one day edit these master switches to control multiple cancer-promoting genes at the same time.

“But there are still important questions to answer before this approach can be translated into new therapies, including the potential side effects of targeting the wrong enhancer,” Rhie said.

Her lab is now studying how enhancer activity plays a role in resistance to existing cancer therapies. They are also working to understand how various enhancers work together in other types of cancer, including breast cancer.

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