Review
Epigenetics and cancer: implications for drug discovery and safety assessment

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Abstract

It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment.

Introduction

Safety assessment is the principal role of the toxicologist and is vital to pharmaceutical and allied industries (such as agrochemicals) as well as government agencies that assess new products. Central to this assessment is the process of carcinogenesis, and many potentially useful products have failed in development or at registration because of a risk of increased carcinogenic potential.

Much effort is being expended to improve the quality of screening to detect potential carcinogens and to discuss and refine the stage in product development where decisions based on toxicological potential can be made.

Historically, toxicologists have focussed on mutagenesis (direct changes in the DNA) as the most appropriate indicator of carcinogenic potential. The last two decades have seen the emergence of non-genotoxic carcinogenesis, the process whereby indirect or epigenetic changes to the genome function contribute to the carcinogenic process.

Here, we describe chromatin structure and its modulation as a basis to explore potential mechanisms of epigenetic modulation. This is placed in the wider context of carcinogenesis and subsequent implications for discovery of therapeutic targets and the safety assessment process.

In this article, which describes a series of presentations from a Continuing Education course at the 2003 Society of Toxicology annual meeting, we define epigenetic modulation as ‘alterations in the expression of genomic information at the transcriptional, translational, or posttranslational level’. By contrast, a genetic, mutagenic, or genotoxic event is the qualitative or quantitative irreversible alteration of genomic information at the gene or macro-chromosome level.

Section snippets

Chromatin structure

Chromatin is a nucleoprotein complex consisting of a basic repeating unit known as the nucleosome. A single nucleosome contains two turns of DNA wrapped around a core histone octamer comprising the histones H2A, H2B, H3, and H4. Nucleosomes represent the first level of compaction in chromatin, restricting access to enzymes involved in DNA metabolism. In addition to these basic components, linker histones and a variety of non-histone proteins are incorporated to generate a fully functional

The role of DNA methylation

Epigenetic regulation of gene expression is based upon modulation of transcription by heritable mechanisms superimposed on that conferred by the primary DNA sequence (Holliday, 1994). DNA methylation is an example of such a mechanism Baylin, 1997, Jones and Laird, 1999, and altered DNA methylation may play a key role in carcinogenesis as an epigenetic, non-genotoxic, secondary mechanism Counts and Goodman, 1995, Goodman and Watson, 2002, Watson and Goodman, 2002. This includes the possibility

The interplay between epigenetic regulation and multi-step carcinogenesis

The classic concept of carcinogenesis describes a multi-stage process consisting of three distinct phases: initiation, promotion, and progression. More recently, several attributes or ‘hallmarks’ have been identified that are universal to all cancers (Hanahan and Weinberg, 2000). These include insensitivity to anti-growth signals, self-sufficiency in growth signals, evasion of apoptosis, limitless potential for replication, and acquisition of the mechanisms required for tissue invasion,

Extranuclear mechanisms of epigenetic regulation

In one sense, epigenetic regulation can refer to the immediate regulation of chromatin structure modification of DNA and its regulating proteins. However, events in the cell nucleus are inextricably linked and therefore, to a degree, regulated by the wider cellular environment. Indeed, the homeostatic control of cellular proliferation, differentiation, and apoptosis has been linked to three highly integrated processes; extracellular, intracellular, and gap junctional intercellular communication

Implications for therapy of human diseases and risk assessment

This review of the literature has identified several epigenetic mechanisms that contribute, in diverse ways, to the carcinogenic process. This has two interrelated implications: novel routes for therapeutic intervention (Brown and Strathdee, 2002) and safety assessment (Feinberg, 2001).

Acknowledgements

The authors wish to acknowledge Dr Andrew Walker PhD, an independent medical communications specialist, for his invaluable assistance in the production of the manuscript.

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