Epigenetics in cancer

Abstract

Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.

Figures

Fig. 1.

Epigenetic gene silencing mechanisms in mammals. (A) An active gene shows an open chromatin structure consisting of an unmethylated promoter region (small white circles on DNA strands), with no nucleosome upstream of the transcription start site (thick black arrow), an enrichment of active histone marks such as acetylation (green triangle, Ac) and H3K4 methylation (green circles, 4) and high levels of H2A.Z on nucleosomes (orange) surrounding the transcription start site. The open chromatin structure is permissible for binding of transcription factors and RNA Pol-II, which mediates active transcription on such promoters. Repression of such active genes (indicated by red arrows) can be achieved in normal cells by two main mechanisms: (B) Gene repression by the action of PRC1 and PRC2 that mediate the repressive H3K27 methylation (red circles, 27) is accompanied by the removal of acetylation by HDACs, loss of H3K4 methylation, chromatin compaction, nucleosome occupancy in the NFR and ubiquitylation of H2A.Z; (C) Long-term silencing through DNA methylation is performed by DNA methyltransferases. DNA methylation (small red circles on DNA strands) is often accompanied by the repressive H3K9 methylation (red circles, 9), on promoters, which leads to chromatin compaction by recruitment of HP1. DNA Methylated-silenced promoters show a depletion of H2A.Z, loss of H3K4 methylation and histone de-acetylation. Ac, acetylation; EZH2, enhancer of zeste homolog 2; HP1, heterochromatin protein 1; K4-HMT, Histone H3 lysine 4 histone methyltransferase; K9-HMT, Histone H3 lysine 9 histone methyltransferase; Pol-II, RNA polymerase II; PRC1 and PRC2, polycomb repressive complex 1 and 2; Ub, ubiquitination.

Fig. 2.

DNA methylation changes in cancer. In normal cells, CpG island promoters are generally unmethylated and when active, as in the case of tumor suppressor genes, are accompanied by active histone marks such as acetylation and H3K4 methylation (green circles, 4) allowing for a transcriptionally active open chromatin structure. However, repetitive regions, transposons, CpG poor intergenic regions and imprinted gene promoters are heavily methylated and accompanied by repressive histone marks such as H3K9 methylation (red circles, 9) that together form a silent chromatin state. During tumorigenesis, tumor suppressor gene promoters with CpG islands become methylated, resulting in the formation of silent chromatin structure and aberrant silencing (indicated by the red arrow). In contrast, the repetitive sequences, transposons and imprinted gene promoters become hypomethylated resulting in their aberrant activation (indicated by the green arrow).

Fig. 3.

Reprogramming of the epigenome during development and tumorigenesis. (A) In ES cells, developmentally important genes are marked by a unique ‘bivalent domain’ structure, consisting of the active H3K4 methylation (green circles, 4) and repressive H3K27 methylation (red circles, 27) marks together with H2A.Z. Such bivalent domains are important for maintaining epigenomic plasticity that is required during development. During differentiation, the bivalent domains are lost, giving way to the establishment of a more rigid ‘monovalent domain’ structure that is either active (indicated by the green arrow) or repressive (indicated by the red arrow) depending upon which mark is maintained. (B) In cancer, cells undergo aberrant somatic reprogramming that results in gene silencing through formation of a compact chromatin structure. Silencing can occur through PRC (Polycomb Repressive Complex) reprogramming—silencing of active genes by the polycomb group; DNA methylation reprogramming—silencing through de novo hypermethylation (small red circles on DNA strands) accompanied by H3K9 methylation (red circles, 9) or epigenetic switching—replacement of gene repression by the polycomb mark with long-term silencing through DNA methylation; Ub, ubiquitylation.