“We are deepening our understanding of the complex processes that turn genes ‘on and off’ in the development of both normal and abnormal tissues,” said Ramin Shiekhattar, Ph.D., Director of the Cancer Epigenetics Research Program, and Chief of the Division of Cancer Genomics and Epigenetics at Sylvester.
Shiekhattar, professor in the Dr. John T. Macdonald Foundation Department of Human Genetics, has studied the DNA and RNA “enhancers” that regulate gene expression, and is lead author of a new study published August 26 in the journal Nature.
“We have learned that these enhancers play a critical role in normal human development, and are also affected by many diseases, including cancer,” he said. “In some cases, an enhancer that is active in a normal cell is silenced by cancer, while in other cases, cancer can activate the enhancer in an abnormal manner.”
Previously, Shiekhattar’s laboratory found a molecular machine called an “integrator complex” that mediates gene activation in cancer cells. In the new study in Nature, his group has identified a critical role for this complex in its regulation of a new type of RNA known as enhancer RNA (eRNA), which is critical for tissue-specific expression of genes. “Enhancer RNAs are a new molecule of life that governs normal and disease states. If the integrator complex doesn’t process the eRNAs correctly, the enhancers do not function properly,” he said.
That was the key finding in the Nature study, “Integrator mediates the biogenesis of enhancer RNAs,” whose co-authors were associate scientist Fan Lai, Ph.D., former associate scientist Alessandro Gardini, Ph.D., and post-doc Anda Zhang, Ph.D., all from Shiekhattar’s lab.
The study has important clinical implications because abnormally high levels of Integrator subunits have been found in more than 50 percent of patients with ovarian, bladder, prostate and breast cancers.
“We have begun looking at new strategies that could affect the progression of cancer at the molecular level,” Shiekhattar said. “If we find compounds that could inhibit the increase in Integrator expression or activity, we might be able to develop a new set of anti-cancer drugs.”
University of Miami