Epigenetic Therapeutics: A New Weapon in the War Against Cancer

Abstract

The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade.

Keywords: DNA methyltransferase inhibitor; epigenetics; histone deacetylase inhibitor therapy.

Figure 1

The epigenome landscape. (a) Chromatin states support either transcriptional activation or silencing of genes, allowing gene regulatory regions to switch these states through positioning of nucleosomes (blue ovals). More open conformations leave the transcription start site nucleosome free. Modifications of nucleosome histone tails ( purple lines extending from ovals) regulate the process, including DNA methylation (red lollipops), serine phosphorylation (orange circle), lysine acetylation (black circle) and lysine methylation ( purple circle), and nucleosome remodeler complexes ( green pentagon with yellow oval). Additionally, noncoding RNAs ( yellow waves) can participate in these regulatory steps through recruitment of chromatin proteins and DNA methylation. (b) Control of histone modifications and of DNA methylation by proteins: writers (DNMTs, HKMTs, HATs, kinases for phosphorylation), readers (shown in subsequent figures for binding to and interpreting each mark for function), erasers (TETs for DNA methylation, HKDMs for lysine methylation, HDACs, phosphatases for removing phosphorylation) and nucleosome remodelers. Red lollipops indicate DNA methylation; green pentagon with yellow oval indicates nucleosome remodeler complexes; purple circle indicates histone lysine methylation; orange circle indicates serine phosphorylation; black circle indicates lysine acetylation. Abbreviations: DNMT, DNA methyltransferase; HAT, histone acetylases; HDAC, histone deacetylases; HKDM, histone lysine demethylase; HKMT, histone lysine methyltransferase; TET, ten-eleven translocation protein.

Figure 2

The four Rs of proteins regulating the epigenome. For open promoter conformation (top), epigenetic signal writers (green circles), readers ( purple circles), and erasers (red circles), and generally no DNA methylation in associated CpG islands ( green lollipops). Nucleosomes (blue ovals) are in an open conformation around the transcription start site (TSS). Writers in the form of histone acetylases (HAT) and histone methyltransferases (HMTs) are enzymes that add acetyl (Ac) and methyl (Me) marks to histone proteins (acetylated lysine, black circles on lollipops; methylated lysine, green circle on lollipop). These modifications to histones cause chromatin conformational changes and gene expression regulation. Readers containing specialized domains bind to these distant marks, which are critical for binding to specific modification states. Erasers such as histone deacetylases (HDACs), lysine demethylases (KDMs), and phosphatases are involved in the removal of epigenetic marks. Transition to an inactive state (bottom) with cancer-specific promoter CpG-island DNA hypermethylation is associated with a more closed nucleosome spacing over the TSS, and HDACs, which erase histone acetylation (gold lollipops), and writers (HMTs) that change active histone methylation marks to repressive ones such as H3K9me3 (blue lollipop) and H3k27me3, as discussed in the text, with HDMs acting as antagonist to HMTs. Another set of writers (DNMT) establish methylation of CpGs at promoter regions (red lollipops), and readers for this methylation are methyl cytosine binding proteins (MBDs). Other abbreviations: DeAc, deacetylation; HDAC, histone deacetylase; HMT, histone methyltransferase; HDM, histone demethylases.

Figure 3

DNA methylation changes in cancer cells. Promoter CpG islands in normal cells (top) generally lack CpG site DNA methylation ( green U lollipops). In cancer (bottom), many genes gain DNA methylation in promoter-region CpG islands with an accompanying repressive chromatin landscape and abnormal gene silencing (red M lollipops).

Figure 4

Treatment approaches based on juxtaposing mutational events and epigenetic alterations. Cancers can have direct effects on the epigenome, resulting from chronic inflammation, viral infections, or microbiome changes, or indirect effects due to mutations in epigenetic driver genes. Epigenetic therapy regimens are evolving (large arrow with circles) for generations of evolving therapies.