Abstract
Alternative splicing (AS) is a critical post-transcriptional regulatory mechanism used by more than 95% of transcribed human genes and responsible for structural transcript variation and proteome diversity. In the past decade, genome-wide transcriptome sequencing has revealed that AS is tightly regulated in a tissue- and developmental stage-specific manner, and also frequently dysregulated in multiple human cancer types. It is currently recognized that splicing defects, including genetic alterations in the spliced gene, altered expression of both core components or regulators of the precursor messenger RNA (pre-mRNA) splicing machinery, or both, are major drivers of tumorigenesis. Hence, in this review we provide an overview of our current understanding of splicing alterations in cancer, and emphasize the need to further explore the cancer-specific splicing programs in order to obtain new insights in oncology. Furthermore, we also discuss the recent advances in the identification of dysregulated splicing signatures on a genome-wide scale and their potential use as biomarkers. Finally, we highlight the therapeutic opportunities arising from dysregulated splicing and summarize the current approaches to therapeutically target AS in cancer.
Highlights
In higher eukaryotes, the primary gene transcripts, called precursor messenger RNAs, undergo a finely tuned post-transcriptional regulatory process that removes the non-coding regions and splices together the coding sequences, generating the mature mRNAs
Due to the different origins of alternative splicing (AS) dysregulation, previously discussed in Section 2.1, aberrant splicing programs in cancer can be targeted in diverse ways, as exemplified in Figure 2, including strategies such as blocking of protein kinases that post-translationally regulate splicing factors, disruption of signaling pathways regulating AS programs, use of oligonucleotides that modulate splicing factor recruitment to the pre-mRNA, targeting of protein isoforms derived from aberrant AS events, or targeting of the components of RNA spliceosome machinery
From a large body of experimental data, it has become increasingly clear that AS is tightly associated with human health and disease [3]
Summary
The primary gene transcripts, called precursor messenger RNAs (pre-mRNAs), undergo a finely tuned post-transcriptional regulatory process that removes the non-coding regions (introns) and splices together the coding sequences (exons), generating the mature mRNAs. AS is a widespread event affecting more than 95% of transcribed human genes, as suggested by data provided by whole transcriptome sequencing projects [2,4] This complex and tightly regulated mechanism is shared across different tissues and developmental stages, and frequently dysregulated in various human diseases, including cancer [5]. This dysregulation was verified in various types of cancer through detection of aberrant splicing patterns in tumor tissues when compared to their normal counterparts by high-throughput sequencing techniques [6,7,8,9]. We highlight the relevance of identifying cancer-specific AS events for the development of novel biomarkers and discuss part of the current therapeutic landscape regarding splicing-based therapies for cancer treatment
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