Targeting epigenetic regulations in cancer

Abstract

Epigenetic regulation of gene expression is a dynamic and reversible process with DNA methylation, histone modifications, and chromatin remodeling. Recently, groundbreaking studies have demonstrated the importance of DNA and chromatin regulatory proteins from different aspects, including stem cell, development, and tumor genesis. Abnormal epigenetic regulation is frequently associated with diseases and drugs targeting DNA methylation and histone acetylation have been approved for cancer therapy. Although the network of epigenetic regulation is more complex than people expect, new potential druggable chromatin-associated proteins are being discovered and tested for clinical application. Here we review the key proteins that mediate epigenetic regulations through DNA methylation, the acetylation and methylation of histones, and the reader proteins that bind to modified histones. We also discuss cancer associations and recent progress of pharmacological development of these proteins.

Keywords: DNA methylation; anti-cancer drugs; epigenetic regulation; histone modification; inhibitors.

Figure 1.

Epigenetic regulation of gene expression Generally, gene expression is controlled in the promoter regions by a combination of DNA methylation and chromatin configuration. In normal cells, active genes are those with open nucleosome spacing around the transcription start site, are unmethylated and associated with acetylated histones. By contrast, gene expression is silenced by condensing chromatin, methylating (at cytosine) DNA, and deacetylating histones. TF, transcription factor; Co-ACT, co-activator; TBP, TATA-binding factor; TAF, TBP-associated factor; RNA-PII, RNA polymerase II. HAT and histone H3 lysine-4 (K4 HMT) are indicated in blue. HDAC and lysine-9 (K9 HMT) are indicated in red. Proteins involved in transcriptional silencing are indicated in red (DNMT, DNA methyltransferase; MBD, methyl-binding domain protein; Co-REP, co-repressor; HP1, heterochromatin protein 1; CAF1, chromatin assembly factor-1).

Figure 2.

Histone modifying enzymes The histone octamer is assembled from a histone H3:H4 tetramer and two H2A:H2B dimers. The histone tails of all four core histones are subject to a variety of post-translational modifications, including methylation (Me), acetylation (Ac), phosphorylation (P), and ubiquitination (Ub). These modifications are controlled by enzymes such as: histone methyltransferases (HMTs) (dark blue), HDMs (purple), HATs (dark green), HDACs (pink), kinases (orange), and ubiquitin-conjugating enzymes (dark red).

Figure 3.

Epigenetic readers Epigenetic reader domains consist of specialized protein–protein interaction motifs, which recognize and discriminate between various post-translational modifications. These domains include: PWWP domains (purple), Chromodomains (light blue), PHD fingers (dark red), MBT domains (light red), Tudor domains (pink), Bromodomains (blue), and Methylation binding (MBT) domains (orange). 5-methylcytosine (5mC) readers (yellow) and 5-hydroxymethylcytosine (5 hmC) readers (green) [133].

Figure 4.

FDA-approved and on-clinical-trial epigenetic drugs for cancer therapy The first generation of FDA-approved epigenetics-based drugs has firmly established that epigenetic modulation is a viable treatment option for a growing list of diseases. So far, epigenetic drugs (especially for DNMT and HDAC inhibitors) have been approved mainly for the treatment of blood cancers, in particular myelodysplastic syndromes (MDS), leukemia, and lymphoma. Recently, HMT and HDM inhibitors start clinical trials for various cancers, including breast cancer, colon center, lung cancer, prostate cancer, ovarian cancer, and neuroblastoma. Epigenetic drugs for cancer treatment including: DNMT inhibitors (red), HDAC inhibitors (black), HMT inhibitors (purple), HDM inhibitors (green), and epigenetic reader inhibitors (blue).