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Inactivation of tumour suppressor genes is central to the development of cancer. Although this inactivation was once considered to be secondary to intragenic mutations, it is now clear that silencing of these genes often occurs by epigenetic means. Hypermethylation of CpG islands associated with the tumour suppressor genes was the first manifestation of this phenomenon to be described. It is apparent, however, that this is one of a host of chromatin modifications which characterize gene silencing. Although we know little about what determines which loci are affected, our understanding of the nature of the epigenetic marks and how they are established has blossomed. There is no compelling evidence that cancer ever develops by purely epigenetic means, but it is apparent that perturbations in the apparatus which establish the epigenome may contribute to the development of cancer. This review will focus on the role of two classes of chromatin remodelling enzymes, those that alter histones by the addition or removal of acetyl and methyl groups and those of the SWI/SNF family of proteins that change the topology of the nucleosome and its DNA strand via the hydrolysis of ATP, and we shall examine the consequence of mutations in, or mis-expression of, these factors. In some cases, mutations in these factors appear to play a direct role in cancer development. However, their general role as important intermediaries involved in regulating gene expression makes them attractive therapeutic targets. In exciting developments, it has been shown that inhibition of these factors leads to the reversal of tumour suppressor gene silencing and the inhibition of cancer cell growth.

Original publication

DOI

10.1093/hmg/ddi106

Type

Journal article

Journal

Hum Mol Genet

Publication Date

15/04/2005

Volume

14 Spec No 1

Pages

R85 - R92

Keywords

Acetyltransferases, Adenosine Triphosphate, Animals, Chromatin, CpG Islands, DNA, Gene Expression Regulation, Neoplastic, Gene Silencing, Histone Acetyltransferases, Histone-Lysine N-Methyltransferase, Histones, Humans, Hydrolysis, Models, Biological, Mutation, Myelodysplastic Syndromes, Neoplasms, Protein Methyltransferases