Zebrafish has offered new hope to people with melanoma, an aggressive form of skin cancer.
Researchers identified 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 J. Houvras, assistant professor of medicine in the Departments of Surgery, Medicine, and Cell and Developmental Biology at Weill Cornell Medical College.
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 that dramatically accelerated melanoma formation: SETDB1, 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 SETDB1 accelerates melanoma formation in zebrafish is important because SETDB1 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 led by first author Richard White, researchers 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.
Houvras explains that the zebrafish is becoming a popular method for investigating malignancies, including melanoma, leukemia and sarcoma.
The study was published in the journal Nature.