Targeting super-enhancer activity for colorectal cancer therapy

Abstract

In addition to genetic variants and copy number alterations, epigenetic deregulation of oncogenes and tumor suppressors is a major contributor in cancer development and propagation. Regulatory elements for gene transcription regulation can be found in promoters which are located in the vicinity of transcription start sites but also at a distance, in enhancer sites, brought to interact with proximal sites when occupied by enhancer protein complexes. These sites provide most of the specific regulatory sequences recognized by transcription factors. A sub-set of enhancers characterized by a longer structure and stronger activity, called super-enhancers, are critical for the expression of specific genes, usually associated with individual cell type identity and function. Super-enhancers show deregulation in cancer, which may have profound repercussions for cancer cell survival and response to therapy. Dysfunction of super-enhancers may result from multiple mechanisms that include changes in their sequence, alterations in the topological neighborhoods where they belong, and alterations in the proteins that mediate their function, such as transcription factors and epigenetic modifiers. These can become potential targets for therapeutic interventions. Genes that are targets of super-enhancers are cell and cancer type specific and could also be of interest for therapeutic targeting. In colorectal cancer, a super-enhancer regulated and over-expressed oncogene is MYC, under the influence of the WNT/β-catenin pathway. Identification and targeting of additional oncogenes regulated by super-enhancers in colorectal cancer may pave the way for combination therapies targeting the super-enhancer machinery and signal transduction pathways that regulate the specific transcription factors operative on them.

Keywords: Epigenetics; enhancers; gene regulation; histone acetylation; promoters.

Figure 1

Schematic representation of super-enhancer structure and key components. A. Trithorax component methyltransferases methylate hIstone 3 at lysine 4 (H3K4). The SWI/SNF component of Trithorax displaces or removes histones using energy from ATP hydrolysis, and sequence specific transcription factors bind their cognate sequences. KAT3 acetyltransferases acetylate histone 3 at lysine 27, creating the signal for BRD4 binding. BRD4 contributes in bringing the super-enhancer bound transcription factors in contact with promoter bound Mediator complex and the general transcription factors that recruit RNA polymerase II to initiate DNA transcription from transcription start sites (TSS). B. The Mediator kinase module displaces the rest of Mediator complex from their interaction with RNA polymerase II and allows transcription to proceed to the elongation phase, after an initial pause is released. Both sequence specific transcription factors and Mediator kinases are under the control of up-stream signal transduction pathways. Small triangles represent H3K27 acetylation and cylinders represent the histone octamer.

Figure 2

Prevalence of mutations in genes of the Mediator kinase module and amplifications of CDK8 in two colon cancer series, The Cancer Genome Atlas (TCGA) colorectal cancer cohort (black bars) and the Sidra-LUMC AC-ICAM colon cancer cohort (Sidra, grey bars).