Silent advances - Innovative Technologies

Environmental Health Perspectives, March 15, 2004 by Carol Potera

A growing body of research shows that gene silencing is a critical component of many diseases. In particular, scientists continue to learn more about how enzymes known as histone deacetylases, or HDACs, work to silence genes. Better understanding of how HDACs silence genes is particularly relevant to understanding, and perhaps better managing, diseases characterized by abnormal cell growth, such as cancer and neurological disorders.

Chromosomes contain DNA, and this genetic material is tightly packed into chromatin. The smallest unit of chromatin is the nucleosome, where proteins known as histones tightly bind DNA. All this wrapping protects genes from being decoded and expressed inappropriately. Histone acetylases switch genes on by freeing DNA from tightly packed chromatin. HDACs are counterpart enzymes that operate in reverse; they shut off genes.

Eleven types of human HDAC were already known to occur in complex mixtures with related proteins, such as gene repressors and hormone receptors. In the course of deciphering the components of one of these complexes, Ramin Shiekhattar, an associate professor in the Gene Expression Program at the University of Pennsylvania's Wistar Institute, discovered an entirely new family of complexes containing HDACs. All the members share a common core composed of HDAC linked to another protein called BHC110. A variety of other proteins are attached to this core unit, including one involved in X-linked mental retardation and another associated with breast cancer. These findings are described in the 28 February 2003 issue of the Journal of Biological Chemistry.

The HDAC section of the new complex binds to chromatin to shut off genes, just like all other HDACs; the challenge lies in uncovering what the BHCllO component does. Scientists have identified enzymes that acetylate, deacetylate, phosphorylate, dephosphorylate, and methylate histones. "What's missing is an enzyme that demethylates histones," says Shiekhattar. He speculates that histone demethylation may actually be the role played by BHC110. If this is indeed the case, "BHC110 is going to be a hot protein," says Shiekhattar.

Another mystery is why diverse proteins are attached to the HDAC/BHC110 core, in contrast to the other HDACs, which bind only one type of protein to their cores. Shiekhattar suspects that the different proteins direct the complex to specific tissues. For instance, one member of the new family contains the ZNF217 gene that is amplified in breast cancer. The HDAC/BHC110 complex with this particular subunit attached may be involved in the regulation of breast cancer. "My gut feeling is that we found a set of complexes that repress different genes based on their unique subunit," says Shiekhattar. Experiments are currently under way to explore this theory.

Shiekhattar's findings add to "the collective work of other laboratories that study HDAC to impact our understanding of diseases," says Danny Reinberg, an investigator at the Howard Hughes Medical Institute and a distinguished professor of biochemistry at the University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School in Piscataway. The overall goal of HDAC research is to learn how HDAC complexes control cellular functions, then identify compounds to block undesirable actions.

For example, defects in the acetylation/deacetylation machinery occur in tumors and in Huntington disease. Scientists at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, led by MSKCC president emeritus Paul Marks, have discovered that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) causes cancer cells to stop growing and die. Their findings are published in the 15 May 2003 issue of Blood. SAHA, which was first synthesized 15 years ago by MSKCC researchers to control the cell cycle, is undergoing clinical trials in cancer patients, who show early positive outcomes. By inhibiting HDAC, SAHA increases the level of histone acetylation, resulting in increased expression of genes and proteins (such as p27kipl and gelsolin) that are directly implicated in tumor suppression.

SAHA has also been shown to prevent movement disorders in a mouse version of Huntington disease, where the buildup of abnormal proteins in brain cells jams the acetylation--deacetylation regulatory system. A team from King's College London published findings in the 18 February 2003 issue of Proceedings of the National Academy of Sciences that mice with the disease that had drunk water laced with SAHA showed significantly less loss of movement than those that drank plain water.

"In years to come, we will learn that other diseases are affected by HDAC," predicts Reinberg. It all goes to show that, as Shiekhattar puts it, gene regulation is "like driving a car"--safe driving relies as much on braking as on accelerating.