The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer

Abstract

Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC.

Keywords: aberrant DNA methylation; chromatin remodelling; histone modifications; long non-coding RNA; microRNA.

Figure 1

Epigenetic functional system in the initiation and progression of CRC. Environmental cues, such as repeated exposure to carcinogens, inflammation, injury, and ageing impinge on epigenetic modulators. These, in turn, destabilize the epigenome through signalling and metabolic pathways. As a result, chromatin states at epigenetic mediator genes are changed triggering their unscheduled expression. Epigenetic mediators can also influence the plasticity of tumour cells during neoplasia, giving rise to the formation of CSCs and metastases. In all these processes, epigenetic modifiers play a central role. Mutations are frequently seen in epigenome modifying genes and, conversely, the epigenetic changes can cause further mutations and genomic instability in modulators. LOF = loss of function; TSG = tumour suppressor gene; GOF = gene of interest; Met = methylation; EMT = epithelial to mesenchymal transition.

Figure 2

Overview of cross-talk between gene-regulatory layers in CRC. This figure depicts selected examples of the deregulated interplay between epigenetic events, alternative splicing (AS) and noncoding RNA in colorectal cancer. See the text of the manuscript for further details. ↑ and ↓ arrows represent up- or down-regulation or higher or lower activity of a factor, respectively. Intron and exons are abbreviated as E or I, respectively. In the cases of AS, ↑ and ↓ represent increased and decreased usage of an exon or intron, respectively. Δ represents isoform switching of a transcript due to AS. SET2D* represents a mutant of SET2D. The dashed arrow with question mark (?) represents a predicted feedback loop between WNT and CCAT-2. A vector graphics version of this figure is provided as Supplementary Figure S1.

Figure 3

Representative drugs targeting epigenetic modifiers. Green colour represents FDA-approved drugs and red colour represents other potential drugs for targeting epigenetics modifiers. Black arrows indicate the reciprocal interplay of epigenetic events with ncRNAs and red arrows represent their effects on the CRC genome and transcriptome.