Histone Researchers Receive Lasker Award

The Albert and Mary Lasker Foundation has honored two scientists whose laboratory investigations elucidated how histones influence gene expression—later shown by the research community to play a role in the development of cancer—with one of its coveted Lasker Awards, which are given annually. Considered to be among the nation's most prestigious biomedical research prizes, the award carries an honorarium of $250,000.

Michael Grunstein, PhD, a professor of biological chemistry at the David Geffen School of Medicine at the University of California, Los Angeles, and C. David Allis, PhD, a professor at The Rockefeller University in New York, NY, and head of its Laboratory of Chromatin Biology and Epigenetics, were named winners of the Albert Lasker Basic Medical Research Award, which was presented in New York on September 21.

Histones were “once regarded as inconsequential DNA packing material, but our honorees have uncovered important links to the control of gene expression and even tumor development,” said Claire Pomeroy, president of the Lasker Foundation. “The work highlights both the beauty of basic research and the importance of basic research to patients battling disease.”

Indeed, “when we started, this study of histones was as basic as basic research could get,” said Grunstein. “They were thought to be unimportant in regulating genes, but no one had ever mutated a histone gene in a living cell and shown what the effects were.”

Taking on that challenge, Grunstein in 1998 engineered yeast lacking the H4 histone. Doing so reduced the number of nucleosomes and increased RNA synthesis of several genes, suggesting that nucleosomes—and the histones that comprise them—can affect DNA transcription. He went on to show that the N-terminus of the histone tail plays a key role in gene expression: A specific lysine located there, when acetylated, interacts with SIR3, repressing transcription. Similarly, he demonstrated that acetylation of other lysines in the histone tail stimulates gene expression.

Allis built on Grunstein's work in 1996. Using Tetrahymena thermophila, a single-celled alga, he isolated an enzyme responsible for acetylating histones: a homolog of GCN5, a known coactivator of transcription in yeast. In subsequent experiments, Allis demonstrated that GCN5 could acetylate certain lysines in histone tails, harkening back to Grunstein's work. Working independently, he and Shelley Berger, PhD, of the University of Pennsylvania in Philadelphia, showed that histone acetylation and gene activity in yeast dropped without GCN5.

Together, these experiments demonstrated that modifying histones through acetylation determined which genes are switched on and off—and when.

“In rapid fashion, their discoveries, and those of many of other investigators, ignited the field,” said Johnathan Whetstine, PhD, of Massachusetts General Hospital in Boston. “We now know that the milieu of nuclear post-translational modifications impact transcription and numerous other processes, such as genome stability.” That's why researchers around the world have launched numerous investigations related to the dynamic regulation of histone modifications, including methylation and phosphorylation.

The findings have had implications for cancer therapeutics. For example, the FDA has approved a handful of histone deacetylase inhibitors, including vorinostat (Zolinza; Merck) for the treatment of cutaneous T-cell lymphoma and panobinostat (Farydak; Novartis) for multiple myeloma. Inhibitors of the EZH2 methyltransferase, such as tazemetostat (Epizyme), are also under development.

The translation of laboratory discoveries from Grunstein and Allis into clinical practice serves as a reminder of the value of basic research and the need for robust funding of studies in simple model organisms—yeast, algae, worms, and flies, for example—not just in human cells, said Whetstine. “Their original observations, those seminal discoveries, weren't born in mammalian cells,” he noted.

“We haven't figured it all out yet,” he continued. “We cannot forget the past or the tools that got us here and how we can apply them to understand normal development and disease.” –Suzanne Rose

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.