ePrints

Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker

Lookup NU author(s): Dr Gordon Strathdee

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

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.

Publication metadata

Author(s): Teodoridis JM, Strathdee G, Brown R

Publication type: Article

Publication status: Published

Journal: Drug Resistance Updates

Year: 2004

Volume: 7

Issue: 4-5

Pages: 267-278

ISSN (print): 1368-7646

ISSN (electronic): 1532-2084

Publisher: Churchill Livingstone

URL: http://dx.doi.org/10.1016/j.drup.2004.06.005

DOI: 10.1016/j.drup.2004.06.005

Notes: Journal Article Review Scotland reviews and commentaries in antimicrobial and anticancer chemotherapy

Altmetrics

Share