WSU researcher receives NIH grant to study how chromatin modifiers regulate cell division

Findings to refine cancer research

The National Institute of General Medical Sciences of the National Institutes of Health recently awarded Lori A. Pile, Ph.D., assistant professor of molecular cell biology in Wayne State University's College of Liberal Arts and Sciences, $1.39 million to research how the alteration of chromatin regulates cellular division and growth. The study is intended to support the development of cancer treatments currently undergoing clinical trials.

Chromatin is a DNA-protein structure that resembles a long DNA "string" wrapped around protein "beads." When certain molecules, called chromatin modifiers, react with the protein beads, the entire chromatin structure either decompresses or coils up tightly. "Chromatin modification depends on whether the proteins were acetylated or deacetylated - in other words, what kind of modifier reacted with the protein," said Pile.

There are two main types of chromatin modifiers. Histone acetyltransferases (HATs) acetylate the proteins, loosening the chromatin structure. Histone deacetylases (HDACs) deacetylate and tighten DNA's grip on the proteins. A correct balance of action of these chromatin modifiers is necessary for normal cell division. Both activities are required for cells to multiply. But when the balance tips in favor of the deacetylation step, cells can multiply too much, Pile said, and cancer is often the culprit.

That is why deacetylation is being targeted by researchers looking for a way to treat patients with cancer. Yet the exact role of HDACs and deacetylation requires more in-depth exploration.

"While a number of chromatin modifiers are currently being tested as anti-cancer agents in clinical trials, the molecular mechanisms behind their cancer-killing properties are not well understood," said Pile. "Our study is anticipated to clarify these mechanisms and refine the molecular tools designed to target cancer."

These "molecular tools" are histone deacetylase inhibitors, or HDIs. To refine HDIs, Pile will uncover the mechanisms of the target, HDAC chromatin modifiers. She will test a particular HDAC called Swi-independent SIN3 and determine whether SIN3 does, in fact, regulate cell growth and multiplication and, if so, how it affects deacetylation and gene repression.

"Inhibiting HDACs, the agents that fuel unregulated cell division, is anticipated to be an effective approach to preventing cancer progression," said Pile.