Six regions in the non-coding parts of the DNA that surround FOXA1, a major prostate cancer driver, may be therapeutic targets for lowering the amount of this cancer-promoting protein — and potentially impairing the growth of prostate cancer cells, a new study suggests.
FOXA1 is involved in a variety of other cancers, but its three-dimensional structure has largely hampered the development of effective inhibitors. The newly discovered regions may present a good alternative to modulate FOXA1 activity, the researchers said.
Titled “Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer,” the study was published in Nature.
A protein found in many parts of the body, FOXA1 has been specifically implicated in the development of prostate cancer. Mutations in the FOXA1 gene, and the DNA sequence that surrounds the gene — which controls the levels of FOXA1 protein — are found in men with early and advanced prostate cancers.
The function of FOXA1 is to bind directly to DNA, allowing genes to be read and proteins to be produced — all supporting the normal function of a cell. However, mutations leading to an abnormal FOXA1, or its overproduction, can lead to aberrant function and the development of cancer.
Despite the knowledge that FOXA1 plays a critical role in prostate cancer, and other cancers such as breast and lung cancers, therapeutic strategies to block its activity are lacking due to difficulties in directly inhibiting FOXA1 activity.
An alternative therapeutic approach now being explored is to block the overproduction of FOXA1.
As FOXA1 production, or expression, is controlled by the DNA that surrounds the gene — the non-coding region — analysis of these regions may provide insight into the regulation of the protein’s production. That could help identify new targets for effective treatment.
This was the approach used by a team of researchers based at the Princess Margaret Cancer Centre, affiliated with the University of Toronto in Canada.
“To track a tumour, we also have to look at the non-coding space in its DNA because that’s where gene expression — the switching on or off of a gene — happens,” Mathieu Lupien, PhD, senior author and an assistant professor at the University of Toronto, said in a press release.
“We can’t dismiss what’s going on in the non-coding space because that is what fuels differences in expression in genes,” Lupien said. “To fully understand a tumour, we have to explore the whole genome — the genes and the non-coding space.”
The research team analyzed the non-coding regions of the FOXA1 gene in tissues isolated from 200 human prostate tumors. They found six mutations in the region of DNA that regulates FOXA1 production — called the promoter — that led to significantly higher levels of FOXA1.
Disrupting this region reduced FOXA1 production, demonstrating its direct connection to FOXA1 expression.
The team demonstrated that these mutations lead to enhanced binding of the proteins that regulate FOXA1 expression. That showed how these changes were responsible for the increased FOXA1 levels.
Further analysis found that these six mutations work together to regulate FOXA1 expression specifically in prostate cancer, and that disrupting these elements impaired the growth of prostate cancer cells.
“Collectively, our results identify cis-regulatory elements within the FOXA1 plexus [network] mutated in primary prostate tumors as potential targets for therapeutic intervention,” the scientists said.
“Gaining insight on the cis-regulatory plexuses of important genes such as FOXA1 in prostate cancer may provide new avenues to inhibit other drivers across various cancer types to halt disease progression,” they concluded.
This discovery allows researchers to expand the tool kit of potential therapies against prostate cancer, according to Lupien, who said this regulatory web represents more precise targets against cancer.