Zebrafish lead way to melanoma gene

CORNELL (US) — Discovery of a new gene may open a path to advanced drug targets to help treat melanoma, an aggressive skin cancer, responsible for about 8,700 deaths each year.

The study, published in the journal Nature, identifies SETDB1 as a new gene that promotes the growth of melanoma and may play a role in up to 70 percent of malignant melanomas.

“We hope our discovery will ultimately lead to better therapeutic strategies for patients with melanoma,” says study co-first author Yariv Houvras, assistant professor of medicine at Weill Cornell Medical College.

For the research Houvras and colleagues created “MiniCoopR,” a transposon-based vector to deliver candidate human test genes into a specially engineered strain of zebrafish that harbors a mutated BRAF gene.

The researchers screened more than 3,000 zebrafish and found one gene, SETDB1, dramatically accelerates melanoma formation:, which encodes a histone methyltransferase enzyme.

Fish melanomas with elevated levels of SETDB1 are highly invasive and have a set of deregulated genes that are present in human tumors with high levels of SETDB1.

The discovery that the enzyme accelerates melanoma formation in zebrafish is important because it also appears to be frequently overexpressed in human melanomas. “SETDB1 is an enzyme, so it may be a good drug target,” explains Houvras.

In a second report from the lab of Leonard Zon at Children’s Hospital in Boston research led by Richard White, found that the combination of leflunomide, a drug used to treat arthritis, and a BRAF inhibitor in clinical development was effective in blocking the formation of stem cells in zebrafish that give rise to melanoma.

“People are surprised when I tell them I use zebrafish to do cancer research,” Houvras says. “It is still amazing to me that the same genes that cause cancer in humans also cause cancer in fish. The zebrafish is an amazing organism because we can do complex genetic studies, and the fish has many of the same organs and tissues that we have.”

The zebrafish is becoming a popular method for investigating malignancies, including melanoma, leukemia and sarcoma, Houvras says.

“The melanoma model allowed us to integrate data from human genomic studies with the zebrafish. This made it possible to create thousands of transgenic animals and look for animals with more aggressive disease.

“The zebrafish is an emerging organism in cancer biology. It has been an important organism for developmental biology and now we want to demonstrate that it has a unique set of attributes that we can use to discover new genes and treatments for patients with cancer.”

Research with zebrafish has a practical side as well. The small, translucent embryos help make some processes, such as angiogenesis or genomic instability, more transparent.

“For the melanoma studies, we designed and executed a study with more than 3,000 adult animals. It would have been very hard to do this kind of research with mice.”

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