Fish shed light on human melanoma

June 18, 2012

A transparent member of the minnow family is providing researchers at Weill Cornell Medical College in New York City with insight into human melanoma – a form of skin cancer – that may lead to new or repurposed drug treatments, for skin and other cancers.

The experiments will be reported at the "Model Organisms to Human Biology: Genetics" Meeting, June 17-20, 2012, at the Omni Shoreham Hotel in Washington, D.C., which is sponsored by the Genetics Society of America. The meeting will bring together investigators who study cancer-relevant biology in model organisms — such as fruit flies, yeast, fungi, worms, and mice — with investigators studying human cancer. Each session includes both speakers from the research community and those focusing on human cancer research.

Each year in the United States, 8,700 people die from malignant melanoma. Yariv Houvras, MD, PhD, at Weill Cornell Medical College and Craig Ceol, PhD, at the University of Massachusetts Medical School, along with their colleagues, discovered that a previously-identified human gene, SETDB1, accelerated the progression of cancer when a copy of the gene was inserted into the zebrafish genome. This led researchers to believe that this gene may have a similar effect in humans. In fish with the human SETDB1 gene, melanomas appear earlier and spread faster, which is easily seen through the transparent skin of the zebrafish.

Zebrafish are valuable models for people. Their generation time is three to four months, and each female lays hundreds of eggs every two to three days. In addition, researchers can easily manipulate its genes, many of which have human counterparts, and they can even see inside the developing embryos because they are transparent.

In the work that will be presented at the meeting on Monday, June 18, the researchers used the fish to probe a part of human chromosome 1 that is involved in melanoma. In humans, cancer gets underway when a sequence of genes mutate, including a key gene called BRAF. About 60 percent of human melanomas have a specific BRAF mutation, and a drug targeting mutant BRAF, Vemurafenib, was approved by the Food and Drug Administration (FDA) last year for the treatment of patients with metastatic melanoma. It's not unusual for cancers to have multiple genetic mutations, so the researchers reasoned that additional genes found in the amplified region on chromosome 1 could also drive .

And that's where the zebrafish came in. The researchers delivered SETDB1 into single-cell zebrafish embryos that already had BRAF mutations, and the resulting adult fish had the human gene in every melanocyte. They discovered that SETDB1 is a master regulator, playing an important role in the regulation of many other genes and accelerating the cancer. SETBD1 acts by altering regions of the genome using a biochemical process called methylation, and in doing so prevents many genes from being turned on and making their appropriate protein products.

Methylation of chromatin is an epigenetic change – that is, it doesn't alter the underlying DNA sequence. SETDB1 acts by binding to DNA and changing the methylation pattern, which it does at several thousand places in the human genome, according to the studies performed by Dr. Houvras and colleagues.

"This is a very exciting area. Many new connections are being made between chromatin-modifying enzymes and cancer," Dr. Houvras explains. The FDA has already approved a drug that inhibits DNA methylation, Decitabine, for a blood disorder called myelodysplasia. "Within the next few years drugs that inhibit histone methylation will be tested in clinical trials. These drugs may target SETDB1 and other histone methyltransferases and help treat specific cancers that rely on these pathways," Dr. Houvras notes.

The zebrafish may be easy to work with, however this project was anything but. The researchers scaled up their experiments to follow several thousand fish for six months. They performed over 35,000 individual observations, Dr. Houvras says, as they watched fish develop melanomas individually.

The role of SETDB1 in the cancer isn't black-and-white. In humans it's highly expressed in 5 percent of normal melanocytes, in 15 percent of benign nevi, and in 70 percent of malignant melanomas. Moles that overexpress the gene may be more likely to progress to cancer, the researchers speculate – which could be very useful information, and all thanks to the zebrafish.

Explore further: New drug, Vemurafenib, doubles survival of metastatic melanoma patients

Related Stories

New drug, Vemurafenib, doubles survival of metastatic melanoma patients

March 1, 2012
A report published this week in the New England Journal of Medicine shows that the 50 percent of metastatic melanoma patients with a specific genetic mutation benefit from the drug Vemurafenib – increasing median survival ...

Second mutation in BRAF-mutated melanoma doesn't contribute to resistance

April 1, 2012
A second mutation found in the tumors of patients with BRAF-mutated metastatic melanoma does not contribute to resistance to BRAF inhibitor drugs, a finding that runs counter to what scientists expected to be true.

Recommended for you

Post-stroke patients reach terra firma with new exosuit technology

July 26, 2017
Upright walking on two legs is a defining trait in humans, enabling them to move very efficiently throughout their environment. This can all change in the blink of an eye when a stroke occurs. In about 80% of patients post-stroke, ...

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.