Keck Medicine of USC researchers discover dual purpose of cancer drug in regulating expression of genes

Contact: Leslie Ridgeway at (323) 442-2823 or lridgewa@usc.edu

LOS ANGELES — Keck Medicine of USC scientists have discovered new clues about a drug instrumental in treating a certain blood cancer that may provide important targets for researchers searching for cures.

The team investigated whether demethylation of gene bodies induced by the drug 5-Aza-CdR (decitabine), which is used to treat pre-leukemia, could alter gene expression and possibly be a therapeutic target in cancer.

“When we put the drug in cancer cells, we found it not only reactivated some tumor suppressor genes, but it down-regulated the overexpressed oncogene (cancer gene),” said Gangning Liang, Ph.D., associate professor of research, Keck School of Medicine of USC Department of Urology, who is corresponding author on the research. “Overexpression is what turns cancer ‘on.’ The mechanism by which the drug accomplishes this dual action is by removing DNA methylation in the gene body, which we didn’t expect.”

DNA methylation is an epigenetic signaling tool used by cells use to turn genes off. DNA methylation is an important component in many cellular processes, including embryonic development. Mistakes in methylation are linked to several human diseases, including cancer.

The research builds upon past research by Peter Jones, Ph.D., D.Sc., former director of the USC Norris Comprehensive Cancer Center, Distinguished Professor of Urology and Biochemistry & Molecular Biology, and now director of research at the Van Andel Institute.

“The beginnings of epigenetic therapy, which is now the standard of care for myelodysplastic syndrome, can be traced back to the discovery of the DNA demethylating effects of 5-Azacytidine at (USC-affiliated) Children’s Hospital Los Angeles in 1980,” Jones said. “Since that time we have always assumed that the drugs act by switching genes on, thus reapplying the ‘brakes’ to cancer cells. In this paper we show that they may also work by turning down the levels of genes, which have become overexpressed in cancer. In other words, they may also decrease the ‘gasoline’ and this two pronged mechanism, which was entirely unexpected, may help explain why patients respond to epigenetic therapy.”

The research, “Gene body methylation can alter gene expression and is a therapeutic target in cancer,” was published online Sept. 25, 2014 in Cancer Cell.

The research is funded by National Institutes of Health grants R37 CA-082422 and RO1 CA-124518.
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Yang, X., Han, H., DeCarvalho, D.D., Lay, F.D., Jones, P.A., & Liang, G. (2014). Gene body methylation can alter gene expression and is a therapeutic target in cancer.
Cancer Cell, Published online Sept. 25, 2014 http://dx.doi.org/10.1016/j.ccr.2014.07.028

ABOUT USC NORRIS COMPREHENSIVE CANCER CENTER

USC Norris Comprehensive Cancer Center has been leading the fight to make cancer a disease of the past. As one of the eight original comprehensive cancer centers in the United States, its mission is to treat and prevent cancer by advancing and integrating education, research, and personalized patient care. For 40 years, USC Norris has been revolutionizing cancer research with innovative surgical techniques and novel cancer treatments. The cancer center’s breakthroughs and discoveries in the field of epigenetics have led the way to a greater understanding of the underlying causes of cancer and new methods of prevention, detection, and treatment. With a multidisciplinary team of more than 250 dedicated scientists and physicians, USC Norris Comprehensive Cancer Center offers patients hope in the battle against cancer.

ABOUT KECK MEDICINE OF USC
Keck Medicine of USC is the University of Southern California’s medical enterprise, one of only two university-based medical systems in the Los Angeles area. Encompassing academic, research and clinical excellence, the medical system attracts internationally renowned experts who teach and practice at the Keck School of Medicine of USC, the region’s first medical school; includes the renowned USC Norris Comprehensive Cancer Center, one of the first comprehensive cancer centers established by the National Institutes of Health (NIH) in the United States; has a medical faculty practice, the USC Care Medical Group; operates the Keck Medical Center of USC, which includes two acute care hospitals: 401-licensed bed Keck Hospital of USC and 60-licensed bed USC Norris Cancer Hospital; and owns USC Verdugo Hills Hospital, a 158-licensed bed community hospital. It also includes more than 40 outpatient facilities, some at affiliated hospitals, in Los Angeles, Orange, Kern, Tulare and Ventura counties.

U.S. News & World Report ranked Keck Medical Center of USC among the Top 10 in ophthalmology (No. 9), and among the Top 25 hospitals in the United States for urology (No. 20) and cancer care (No. 23). The medical center was also awarded an “A” grade from The Leapfrog Group in March, representing outstanding patient safety practices and overall patient outcomes.

For more information, go to www.keckmedicine.org/beyond