Drug Resistance Updates 7 (2004) 267–278 Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker Jens M. Teodoridis, Gordon Strathdee, Robert Brown ∗ Centre for Oncology and Applied Pharmacology, CRUK Beatson Laboratories, Glasgow University, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK Received 21 June 2004; accepted 28 June 2004 Abstract Many genes become transcriptionally silenced during the development of cancer. As well as affecting disease progression, gene silencing has the potential to influence drug resistance and clinical outcome following therapy. In addition to silencing due to gene mutations, covalent epigenetic modifications such as DNA hypermethylation and histone post-translational modifications are associated with transcriptional inactivation of many genes and are an important early event during carcinogenesis and tumour development. Aberrant methylation of CpG islands in promoters is associated with transcriptional inactivation of genes involved in all aspects of tumour development. Genes involved in key DNA damage response pathways, such as cell cycle control, apoptosis signalling and DNA repair, can frequently become methylated and epigenetically silenced in tumours. This may lead to differences in intrinsic sensitivity of tumours to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, it is proposed that chemotherapy itself can exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Since the DNA sequence of epigenetically inactivated genes are not mutated but rather subject to reversible modifications via DNA methyltransferases (DNMTs) or histone modification, it is possible to reverse silencing using small molecule inhibitors. Such compounds show anti-tumour activity and can increase the sensitivity of drug resistant preclinical tumour models. Clinical trials of epigenetic therapies are now underway. Epigenetic profiling, using DNA methylation and histone analysis, will provide guidance on optimisation of these therapies with conventional chemotherapy and will help identify patient populations who may particularly benefit from such approaches. © 2004 Elsevier Ltd. All rights reserved. Keywords: Methylation; Epigenetics; DNMT; Histones; CpG-islands 1. Epigenetic silencing plays a crucial role in tumour development Epigenetic change can be defined as a stable change in gene expression inherited through subsequent cell divisions, which is not due to a change in DNA sequence. The only known epigenetic modification of DNA itself is the transfer of a methyl group to the carbon 5 position of cytosines, almost always in the context of CpG dinucleotides. This reaction is catalysed by members of the family of DNA methyltrans- ferases (DNMT), DNMT1, DNMT3a and DNMT3b (Bird and Wolffe, 1999; Liu et al., 2003a). DNMT1 which is associ- ∗ Corresponding author. Tel.: +44 141 330 4335; fax: +44 141 330 4127. E-mail address: r.brown@beatson.gla.ac.uk (R. Brown). ated with the DNA replication complex (Vertino et al., 2002), binds preferentially to hemimethylated DNA and functions primarily to maintain methylation patterns after DNA repli- cation. Mice with low levels of expression of DNMT1 show genomic hypomethylation and are prone to develop lym- phomas, although they can have a lower incidence of other types of tumours (Gaudet et al., 2003; Laird et al., 1995). Overexpression or complete loss of DNMT1 results in loss of genetic imprinting and is embryonic lethal (Biniszkiewicz et al., 2002; Li et al., 1993). DNMT3a and DNMT3b act mainly as de novo methyltransferases establishing methy- lation patterns during development, although there is evi- dence that DNMT3a and DNMT3b can maintain methyla- tion patterns in mouse embryonic stem cells (Chen et al., 2003). 1368-7646/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.drup.2004.06.005