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by Olga Kuchment
Some genes are like stories that let readers choose between several endings. Take the gene KLF6, for instance.
The way a person's cells read KLF6 can result in a protein that drives growth or one that slows it. That decision makes a difference in prostate cancer, according to research by Goutham Narla, a recent winner of an HHMI Early Career Physician-Scientist Award.
Ten years ago, when Narla was an HHMI medical research fellow, he made a discovery that helped characterize KLF6 as a tumor suppressor gene that is blocked in prostate cancer. The work was an outgrowth of research on the liver; Narla trained, as a medical student and then as an M.D./Ph.D. student, in the laboratory of Scott L. Friedman, a physician-scientist at New York's Mount Sinai School of Medicine who studies liver disease.
With Friedman and colleagues, Narla, who launched his own lab at Mount Sinai in 2006, recently revealed that KLF6 also encodes a protein that drives cancer development and progression. On the basis of this discovery, they've proposed ways to predict a man's risk of developing prostate cancer and whether the disease, once diagnosed, is likely to recur. In 2008, they designed what may one day be a new treatment for the most aggressive forms of the disease.
In 1998, Friedman was studying a class of cells (hepatic stellate cells) involved in liver healing. His lab group had found that when these cells reproduced, KLF6 was active. Although every cell in the body expressed KLF6, Freidman wanted to know the gene's role in the liver. As an HHMI medical fellow, Narla engineered mice with overactive KLF6 in the liver.
The mice were unusually small—with small livers. At the time, “we thought, maybe this gene actually tells cells to stop growing,” Narla recalls. He tested the idea and discovered that KLF6 engages well-known cellular machinery for growth suppression—specifically, tumor suppression.
Narla scoured the literature and found that many patients' prostate tumors have DNA damage in a region of the chromosome that includes KLF6. He dissected human prostate tumors and confirmed that most lacked one copy of KLF6 or had mutations in the gene. Moreover, when he activated KLF6 in cultured tumor cells, the cells grew more slowly.
Illustration: Paul Sahre