Harnessing the potential of epigenetic therapy to target solid tumors

Abstract

Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer.

Figure 1. Various classes of epigenetic modifiers.

The epigenetic machinery consists of components that catalyze the covalent modifications of histone tails or the DNA (writers). These marks are interpreted by proteins (readers) that bind to the epigenetic marks, resulting in regulation of gene expression. Another class of proteins (erasers) reverses the epigenetic marks by catalyzing their removal. A class of protein complexes (movers) catalyzes the shifting of nucleosomes, resulting in a compact or relaxed chromatin. Here, the broad importance of these proteins in the context of gene silencing is shown. Writers acting separately on histones and DNA result in inactive histone modifications and CpG methylation. Erasers (such as LSD1) remove active histone modifications. Protein readers that bind to active histone (black lollipops) marks (e.g., bromodomain containing 4) are shown in green, those binding to inactive histone (white lollipops) marks (e.g., heterochromatin protein 1, chromobox homolog 7) are shown in pink, and those binding to methylated CpG (green lollipop denotes unmethylated CpG; red lollipop denotes methylated CpG) are shown in brown. The histone movers are shown to play a role in compacting chromatin. Once silenced, a gene will be maintained in the silenced state across cell divisions via recruitment of the writers in every cell cycle.

Figure 2. Model for initiation of DNA methylation-mediated gene silencing.

(A) Left panel: Methylation of CpGs at the borders of CpG islands in normal cells is mediated by the DNMTs as a complex with the HDACs, PRC4 complex (PRC2 component of PcG including SIRT1) with potential involvement of nucleosome remodelers (NuRD). In normal cells, the DNA methylation machinery is restricted from CpG islands, thus protecting these regions from methylation. Right panel: Movement of the repressive complex into the CpG island with stress and associated gene silencing, marked with a red X. However, most genes revert back to the normal cell state. (B) Left panel: A subset of genes with CpG island promoters in embryonic and adult stem cells have both the active (H3K4me3) and inactive (H3K27me3, PcG mark) marks at their promoters, termed “bivalent” marks, in which the genes have a low but poised expression state. Genes that are hypermethylated in cancers frequently have such bivalent marks in the embryonic and adult stem cells. When repetitive insults to cells, such as inflammation, recruit the DNA methylation machinery into the CpG islands of these vulnerable genes, this can initiate abnormal methylation for some of these genes (far right panel). The NuRD complex, a key platform for HDAC1 and -2, may be a part of the complex that maintains silencing of the methylated CpG islands containing genes. Various components of the epigenetic machinery that mediate gene silencing are being targeted already (red ovals), and others are potential targets (green ovals) for cancer therapy.

Figure 3. Gene expression changes in multiple pathways associated with epigenetic therapy.

Treatment with well-tolerated, low doses of epigenetic therapy over multiple cycles initiates widespread changes in gene expression in multiple pathways, including cell cycle, cell adhesion, and apoptosis, that may induce tumor regression or sensitize to chemotherapy. These concepts are currently in clinical trials. Activation of the immune responses such as antigen presentation is also a promising strategy for synergy with immunotherapy.