(PHILADELPHIA—Thursday, July 1, 2004)—First discovered twenty years ago, the cancer gene MYC is the most overexpressed oncogene in human cancers. But only in recent years have scientists begun to unravel MYC’s complex workings in an effort to develop therapies that would block MYC’s function in cancer. The promise of therapies targeting MYC appears especially great; MYC mutations are associated with a wide range of common cancer types, including breast, colon, ovarian and prostate cancers, and melanoma.
Recent studies have determined that the MYC protein, known as a transcription factor, binds to about 15 percent of all genes. Scientists had long believed that when MYC binds to a target gene, it turns that gene on, or activates it. Surprisingly, new work by Steven B. McMahon, Ph.D., assistant professor at The Wistar Institute, and others demonstrates that MYC frequently binds to genes without activating them. In an article for Nature Reviews Cancer published online today and in the July print issue, McMahon’s research team offers a reanalysis of several previous studies of MYC’s binding to target genes. The unexpected discovery that MYC binds to a large percentage of genes without activating them calls into question long-held assumptions about MYC’s functioning and opens new directions for MYC research, McMahon says.
“These previous studies looked at which genes are bound by MYC, and it turns out to be a great percentage of genes—one out of every six,” McMahon says. “Our work has extended what these studies hinted at: contrary to what was believed, MYC doesn’t always turn on the genes to which it binds. The implication is that just figuring out which genes bind to MYC will not be enough to tell us what pathways are being activated in cancer. There must be other factors that play a role in whether MYC activates a gene.”
McMahon worked with colleague Louise C. Showe, Ph.D., associate professor at The Wistar Institute and scientific director of Wistar’s genomics and microarray facility, on the reanalysis of the data from the previous MYC studies. Microarray technology enables scientists to study the activation patterns of thousands of genes at once instead of looking at single genes. Such analyses have become possible only in recent years, with the sequencing of the human genome and the development of powerful computers and computational methods for sorting through the data.
The discovery that MYC binds to so many genes without necessarily activating them raises new questions for cancer researchers. Does MYC have other functions besides activating genes? Are there other unknown factors that play a role in whether MYC activates a gene? “There are many other processes besides activation that MYC might be regulating,” McMahon says. “It’s also possible that there might be tissue-specific controls related to MYC binding.” He notes that perhaps MYC binds to a given gene in all cell types but only activates that gene in a specific organ.
Another question is whether this phenomenon of binding without activating may occur with other transcription factors besides MYC. “These kinds of studies and the technology enabling them are so new that many of these questions haven’t yet been addressed,” McMahon says.
Already biotechnology companies are developing cancer drugs directed at MYC, but current efforts involve drugs that would block all MYC function. Understanding the specific targets of MYC and their involvement in cancer should ultimately allow scientists to create better drugs that would only block MYC function in cancerous cells, thus reducing toxicity, McMahon says.
With McMahon, the other co-authors were Jagruti H. Patel, Andrey P. Loboda, Ph.D., Michael K. Showe, Ph.D., and Louise C. Showe, Ph.D. Funding for the work was provided by the National Institutes of Health and the Pennsylvania Department of Health’s Commonwealth Universal Research Enhancement Program.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center — one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
© 2004 The Wistar Institute
Patel JH, Loboda AP, Showe MK, Showe LC, McMahon SB.
Opinion: Analysis of genomic targets reveals complex functions of MYC.
Nat Rev Cancer. 2004 Jul;4(7):562-8.
Message posted by: Frank S. Zollmann
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