The study sheds light on the enzyme’s role in the advanced progression of prostate cancer

Prostate cancer is the most common cancer in men other than skin cancer, and more than 288,000 new cases are diagnosed each year, according to the American Cancer Society. The disease’s death rate has more than halved since the 1990s, but there is still room for progress—especially in treating or preventing advanced, metastatic disease, which is much more likely to be fatal.

A new paper published in Advances in Science elucidates how an enzyme called SMYD3 may be involved in the progression of prostate cancer to a more dangerous and aggressive stage. The newly confirmed role of the enzyme makes it a prime potential drug target for the prevention of metastatic disease.

Redefining the role of an enzyme

Researchers have been trying to explain SMYD3’s role in cancer since noticing that it is unusually abundant in cancerous tumors compared to healthy tissue, explains Erin Green, associate professor of biological sciences at the University of Maryland, Baltimore County (UMBC) and senior author at work. .

“There is a lot of interest in this protein,” says Green. “However,” he adds, “the literature is confused.”

Several previous studies suggested that SMYD3 acted inside a cell’s nucleus and regulated which genes the cell expressed by directly modifying DNA. But research led by Nicolas Reynoird, a scientist at the Institute of Advanced Biosciences in Grenoble, France and co-author of the new study, suggested a different mechanism.

In a seminal 2014 paper published while Reynoird was a postdoctoral fellow at Stanford, he and his colleagues found that SMYD3 worked outside the nucleus and activated a type of protein called MAP kinase. MAP kinases are overactive in cancer cells and can promote tumor growth.

New Advances in Science paper, led by Sabeen Ikram, a postdoctoral fellow at Stanford University, built on Reynoird’s earlier work. Ikram’s experiments showed conclusively and in detail how SMYD3 can trigger metastatic prostate cancer through the MAP kinase signaling pathway. The new paper links SMYD3 overabundance and excessive activation of MAP kinase signaling for the first time in prostate cancer, renewing interest in SMYD3 as a therapeutic target.

Exciting finds from every angle

The research team showed in cells in a petri dish and in mice that the addition of methyl groups (one carbon atom attached to three hydrogen atoms) to MAP kinase is likely SMYD3’s role in driving metastasis. Experiments with inactivated SMYD3 were much less likely to result in metastasis.

Compounds that can disable SMYD3, called inhibitors, are already available, Green says. Ikram experimented with one of these and found that it effectively killed cancer cells in a Petri dish. The team would like to perform the same experiments in mice to further confirm the effect of the compound. They would also like to investigate whether targeting SMYD3 could help treat cancers that develop resistance to other treatments.

Ikram’s experiments also found that SMYD3 led to increased activity of a protein called vimentin, which has been well studied as a marker of cancer progression. Interestingly, the effect of SMYD3 was specific to vimentin, even though it is a member of a large group of similar proteins.

Finally, the new study found for the first time that SMYD3 creates a positive feedback loop in the cell, where high levels of SMYD3 help maintain its overabundance.

A new direction and new hope for patients

Green sees many avenues for future work.

We’ve only tested this mechanism in prostate cancer so far, but I think it’s likely to happen in other types of cancer cells as well. That’s another thing we want to continue to investigate: How common is this?”

Erin Green, Associate Professor of Biological Sciences, University of Maryland, Baltimore County (UMBC)

Green is also excited about the potential use of SMYD3 as a therapeutic target for prostate cancer or other cancers. SMYD3 inhibitors already exist, so the new findings may encourage companies to invest in discovering new uses for them.

“There are drugs out there that haven’t been fully explored because people decided there wasn’t a good target,” Green says. “So there’s a lot more that could be done there.”