Epigenetic plasticity of enhancers in cancer

Abstract

Enhancers are cis-acting elements with many sites bound by transcription factors and activate transcription over long distance. Histone modifications are critical for enhancer activity and utilized as hallmarks for the identification of putative enhancers. Monomethylation of histone H3 lysine 4 (H3K4me1) is the mark for enhancer priming; acetylation of histone H3 lysine 27 (H3K27ac) for active enhancers and trimethylation of histone H3 lysine 27 (H3K27me3) for silent enhancers. Recent studies from multiple groups have provided evidence that enhancer reprogramming, especially gain of enhancer activity, is closely related to tumorigenesis and cancer development. In this review, we will summarize the recent discoveries about enhancer regulation and the mechanisms of enhancer reprogramming in tumorigenesis, and discuss the potential application of enhancer manipulation in precision medicine.

Keywords: Enhancer; H3K27ac; H3K27me3; H3K4me1; cancer; histone modification.

Figure 1.

Histone modification enzymes regulating enhancers. A brief summary of epigenetic enzymes including “writers and erasers” regulating enhancer activity. MLL3/4 and CBP/p300 are responsible for building up the hallmarks of enhancers, H3K4me1 and H3K27ac, respectively. While, some of the enzymes may regulate enhancers through recruiting other enzymes or cofactors, independent of their catalytic activity.

Figure 2.

Mutations in enhancer-associated factors. The percentage of patients affected by the indicated gene mutations in all types of cancers is shown. PTEN (phosphatase and tensin homolog) is a well-known tumor suppressor and used as comparison here. Data are from TCGA database. KMT2D, lysine methyltransferase 2D, also named as MLL4; KDM2C, lysine methyltransferase 2D, also named as MLL3; CREBBP, CREB binding protein, aslo named as CBP; EP300, E1A binding protein p300, also named as p300; KDM6A, lysine demethylase 6A, also named as UTX; rack, lysine demethylase 5C, also named as JARID1C; KDM3A, lysine demethylase 3A, also named as JMJD1A; KDM1A, lysine demethylase 1A, also named as LSD1; KAT5, lysine acetyltransferase 5, also named as TIP60; SETD7, SET domain containing 7, also named as SET7/9.

Figure 3.

Enhancer reprogramming in tumorigenesis. (a) Overview for the hyper-active enhancer activity of oncogenes in cancer cells. Pioneer factors, such as FOXA1, HOXA9, and TP63, bind to enhancers and facilitate the recruitment of co-factors, such as p300, to promote oncogenic enhancer activity. Moreover, some tumor suppressors, such as KDM5C, are mutated which promotes the hyper-activation of oncogenic enhancers. (b) Overview for the repression of tumor suppressive enhancers in cancer cells. The key enzymes for enhancer regulation including p300/CBP and MLL3/4 are frequently mutated in cancer cells. SNPs in enhancers can destroy transcription factor binding sites, directly inactivating enhancers and leading to transcriptional down-regulation of tumor-suppressor genes.