Epigenetic cross-talk between DNA methylation and histone modifications in human cancers

Abstract

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.

Keywords: DNA methylation; Histone methylation; histone methyltransferase.

Fig. 1

Schematic of histone modifications and modifiers. (A) DNA is compacted in the nucleus. The fundamental repeating unit of chromatin is the nucleosome, which consists of 147 base pairs of DNA wrapped around an octamer of the following core histone proteins: H2A, H2B, H3, and H4. Histone proteins consist of less structured amino-terminal tails (tail domain) that protrude from the nucleosome and globular carboxy-terminal domains make up the nucleosome scaffold (fold domain). The histone tail domain could be a target of a variety of post-translational modifications, including acetylation (Ac), methylation (Me) and ubiquitination of lysine (K) residues, phosphorylation (P) of serine (S) and threonine (T) residues, and methylation of arginine (R) residues. (B) Lysine residues in the histone H3 tail are the targets of methyltransferases and demethylases. Histone methylase, MLL, myeloid/lymphoid or mixed-lineage leukemia; SMYD3, SET and MYND domain containing 3; RIZ1, retinoblastoma protein-interacting zinc-finger protein 1; EZH2, enhancer of zeste homologue 2; NSD1, Nuclear receptor binding SET domain protein 1. Histone demethylases, LSD1, lysine-specific histone demethylase 1; SMCX, Smcx homolog, X chromosome; SMCY, Smcy homolog, Y chromosome.

Fig. 2

Bivalent histone modification in ES cells resolve during differentiation. In embryonic stem cell (ES cells), active mark histoneH3 lysine 4 di-methylation / tri-methylation (H3K4me2/3) and repressive mark histoneH3 lysine 27 trimethylation (H3K27me3) coexisted (bivalent modification status) on development-related genes, which might be necessary for sustaining an undifferentiated state. The bivalent modifications in their promoter regions resolved during ES cell differentiation into either H3K27me3 or H3K4me3 domains.

Fig. 3

Two distinct histone modifications for gene silencing in human cancers. In cancer cells, interactions between DNA methylation and histone H3K9 methylation have been observed, which may contribute to forming and reinforcing a silencing loop leading to stable silencing machinery. A polycomb group (PcG) protein, enhancer of zeste 2 (EZH2), which is a member of the polycomb repressor complex 2 (PRC2), has a histone methyltransferase activity with substrate specificity for H3K27. H3K27triM serves as a signal for specific binding of the chromodomain of another polycomb repressor complex, PRC1. Binding of PRC1 blocks the recruitment of transcriptional activation factors, and the presence of PRC1 prevents initiation of transcription.

Fig. 4

Model of de novo DNA methylation and de novo histone modifications in human cancers. The bivalent modifications in ES cells were resolved during differentiation into H3K4me3 domains when genes are actively transcribed. Exposure to chronic inflammation or a carcinogen leads to an imbalanced histone modification that is not normally observed. Subsequently, as part of an aberrant regulatory program in cancer, de novo H3K27me3 occupies the promoter regions, which are not occupied by PcG protein in ES cells (major target genes have non-CpG promoters). In this situation, the two epigenetic mechanisms, PRC and DNA methylation, do not overlap each other. A subset of promoters (CpG promoters), which are initially marked by the PcG complex in ES cells, become DNA hypermethylated. PRC marks are reduced during or after the establishment of DNA hypermethylation. This epigenetic switch to DNA methylation-mediated repression reduces epigenetic plasticity, locks the silencing of key regulators and contributes to tumorigenesis. In some genes, H3K27me3 and DNA methylation co-exist on the same promoter and PcG-mediated H3K27me3 appears to be the dominant silencing machinery.