Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs

Abstract

The epigenome is a key determinant of transcriptional output. Perturbations within the epigenome are thought to be a key feature of many, perhaps all cancers, and it is now clear that epigenetic changes are instrumental in cancer development. The inherent reversibility of these changes makes them attractive targets for therapeutic manipulation, and a number of small molecules targeting chromatin-based mechanisms are currently in clinical trials. In this perspective we discuss how understanding the cancer epigenome is providing insights into disease pathogenesis and informing drug development. We also highlight additional opportunities to further unlock the therapeutic potential within the cancer epigenome.

Keywords: Cancer; chromatin; epigenome; histone modification; targeted therapy.

Figure 1. Chromatin writers, readers and erasers in epigenetic gene regulation

The addition of histone post-translational modifications is catalyzed by a class of enzymes known as chromatin “writers”. The modifications established by these writers may affect gene transcription by altering electrostatic interactions within or between adjacent nucleosomes. Alternatively they may act as binding substrates for another class of chromatin regulators called chromatin “readers”. Chromatin readers employ characteristic binding domains, such as chromo-, bromo-, and PHD-finger domains to bind nucleosomes marked by specific modifications, or a combination of modifications. Chromatin readers may themselves possess additional chromatin modifying activities, or alternatively recruit additional proteins to modify the local chromatin environment. Finally, chromatin “erasers” catalyze the removal of histone modifications, thereby reversing their biochemical effects on the chromatin fiber.

Figure 2. Targeting the oncogenic function of EZH2 in lymphoma and solid tumors

Heterozygous point mutations of the EZH2 SET domain in non-Hodgkin lymphomas leads to an enhanced accumulation of H3K27me3 on the promoters of PRC2 target genes in Germinal Center B-cells (Upper panel). This causes aberrant silencing of these genes, many of which are required for terminal B-cell differentiation and cell cycle exit. Small-molecule inhibitors (right panels) of EZH2 enzymatic activity are currently in clinical trials for the treatment of lymphoma patients with activating EZH2 mutations. Moreover, these molecules are also in trials for the treatment of SNF5-deficient malignant rhabdoid tumors (MRTs) where SNF5-loss facilitates aberrant EZH2-mediated silencing of SNF5 target genes, such as the tumor suppressor CDKN2A (lower panel).

Figure 3. Targeting MLL-rearranged leukemia through co-opted DOT1L activity

Studies have demonstrated that MLL-fusion proteins, such as MLL-AF9, recruit aberrant chromatin activity in the form of DOT1L mediated H3K79me2 to the promoter of MLL-fusion target genes in primitive hematopoietic cells. DOT1L activity is essential for the expression of MLL-fusion target genes such as HOXA9 and MEIS1, and this requirement has been exploited through the development of small-molecule inhibitors of DOT1L enzymatic activity (Right panel). DOT1L inhibitors are currently in clinical trials for the treatment of MLL-rearranged leukemia.

Figure 4. Defining the epigenomic changes in cancer

The alteration of a single chromatin modifying activity in cancer cells is known to have profound affects on the landscape of additional related chromatin modifications and other chromatin regulators. These alterations are likely instrumental in disease pathogenesis; however until recently our ability to systematically annotate such changes has been limited. The use of unbiased quantitative mass spectrometry techniques holds great promise for the annotation of chromatin dynamics in response to cancer promoting alterations in epigenetic pathways. This may facilitate the identification of additional therapeutic targets within the cancer epigenome.