Environmental Factor, April 2007, National Institute of Environmental Health Sciences
USC Specialist Discusses Epigenetic Therapy
By Eddy Ball
The latest talk in the NIEHS 2006-2007 Distinguished Lecture series on March 13 featured University of Southern California (USC) Distinguished Professor of Urology Peter Jones, Ph.D. Jones is director of the USC/Norris Comprehensive Cancer Center in the Kirk School of Medicine and holds the H. Leslie Hoffman and Elaine S. Hoffman Chair in Cancer Research. The topic of his lecture was "How the Epigenome Changes in Cancer."
Lecture host and Laboratory of Molecular Carcinogenesis Chief Trevor Archer, Ph.D., opened the event by reviewing some of the highlights in Jones' distinguished career. "Early in his career, Peter made a very seminal set of discoveries, hailed in Nature as 'one of the milestones in cancer research,'" he observed. "Peter and his group demonstrated for the first time the causative relationship between methylation and gene expression and differentiation changes."
In the years that followed, Jones and his group translated their findings into development of therapeutics and treatments now in various stages of pre-clinical and clinical trials. His work has been inspired by the conviction that epigenetic aberrations involved in cancer development are potentially reversible.
Jones believes that epigenetic therapy has the potential to return the malignant cell population to what he described as "a quasi-normal state."
During his talk, Jones focused on two major inter-related cancer-promoting processes that are the targets of his drug development efforts, DNA methylation and histone modification. By altering nucleosome occupation patterns, these processes work together to silence expression of tumor-suppressor genes and other genes that are critical to normal cell function.
Using an aerial photo of the earth at night, Jones invoked the image of light as an analogy for gene transcription. "So what goes on in cancer?" he asked. "The lights go out.... [and] several genes can be actually inactivated and switched off."
According to Jones, DNA methylation patterns, once established, can be copied and serve as a very powerful way of silencing genes. "Physiologically this [methylation] is essential for life," Jones explained, "and pathologically if it goes wrong it gives rise to cancer."
The enzyme DNA methyltransferase (DNMT) is responsible for triggering DNA methylation. When methylation occurs near the transcription start site, it silences genes that suppress tumor development. Drugs that target DNMTs are thus potentially useful in treatment.
The other important enzymatic process that Jones discussed is histone modification. Histones are basic proteins in nucleosomes that are wrapped in DNA. Their tails are subject to post-transcriptional alterations. Although there are several ways that histones may be modified, Jones focused on the deacetylation of lysine residues on histone tails, which results in chromatin compaction and inactivation of genes.
The enzyme involved in this process is histone deacetylase (HDAC). Loss of lysine acetylation through activation of HDAC has been identified as the first step in gene silencing. Loss of acetylation also leads to a decrease in DNA repair, further promoting cancer development and profliferation.
Jones and his group have studied more than twenty compounds shown to inhibit DNMTs and HDACs. As promising as many of these drugs are by themselves, especially for inhibiting these enzymes before lesions have actually occurred, they are not as effective as a stand-alone therapy after tumors have developed. Some of the drugs already approved or in trial are very short acting, and their effects can be transitory.
Jones suggested that the future of epigenetic therapy for cancer will probably involve chronic therapy with a combination of primary and secondary treatments. Such an approach would utilize a standard cancer tool, such as chemotherapy, immunotherapy or radiotherapy, in conjunction with enzyme inhibitors. Epigenetic drugs could set the stage for more effective treatment by reactivating tumor-suppressor genes and restoring DNA repair to improve the patient's response to other drugs and to make cells more chemo-sensitive to standard therapies.