Their findings, which have been published online as “The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation” by the journal Proceedings of the National Academy of Sciences, may lead to the development of new drugs with increased effectiveness against brain tumors.
Glioblastoma Multiforme (GBM) is the most common and deadliest primary brain tumor in adults. Despite aggressive treatment, median survival is approximately 14 months, and there is an urgent need for novel therapies.
“For many years, investigators have been studying conventional genes in brain tumors, but arguably no complete picture has emerged,” said Claes Wahlestedt, M.D., Ph.D., Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, Associate Dean for Therapeutic Innovation, and a principal author of the journal article. “We instead focused on the huge area of so-called ‘dark matter’ of the human genome, which is essentially uncharted territory. Our research team has been building expertise to study these unknown parts of the genome for a long time, and we have found that they play an absolutely crucial role in the growth of these tumors.”
Epigenetic modulators, such as bromodomain proteins, are considered important therapeutic targets in cancers, including GBM. Bromodomain inhibitors suppress proliferation by repressing oncogenes and inducing tumor suppressor genes through largely unidentified pathways.
“We demonstrated that the molecule HOTAIR is often massively overexpressed in GBM, where it is crucial to sustain tumor cell proliferation, and that inhibition of HOTAIR expression by bromodomain inhibitors is necessary to induce cell cycle arrest in GBM cells,” said co-author Nagi Ayad, Ph.D., associate professor of psychiatry and behavioral sciences. “Our study helps understand the mechanism of action underlying the anti-proliferative activity of this new drug class, showing for the first time that the oncogenic long noncoding RNA HOTAIR is a major factor in driving tumor growth.”
This novel study produced completely unexpected results.
“We learned two important things,” said Wahlestedt. “First, that this dark matter of the genome is crucial for the growth of these types of brain tumors. Second, that an important new type of drug currently being tested in patients with brain tumors actually works, at least in part, by modifying this dark matter of the genome.
“We and others can use these findings to develop drugs for brain tumors that are hopefully more effective than the treatments we have today. Our study describes not only HOTAIR, but also other so-called long noncoding RNAs that could conceivably be used as biomarkers by which we and others can monitor the effectiveness of these new drugs.”
Additional Miller School of Medicine authors are first author Chiara Pastori, Ph.D., postdoctoral fellow at the Sylvester Comprehensive Cancer Center; Ricardo Komotar, M.D., Director of Surgical Neuro-oncology at UHealth – University of Miami Health System; Clara Penas, Ph.D., research associate in the Ayad laboratory; Veronica Peschansky, M.D./Ph.D. student; Claude-Henry Volmar, Ph.D., associate scientist in the Department of Molecular and Cellular Pharmacology; and Amade Bregy, M.D., Ph.D., Director of Research Support in the Department of Neurological Surgery.
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