Abstract
Alternative splicing allows for the expression of multiple RNA and protein isoforms from one gene, making it a major contributor to transcriptome and proteome diversification in eukaryotes. Advances in next generation sequencing technologies and genome-wide analyses have recently underscored the fact that the vast majority of multi-exon genes under normal physiology engage in alternative splicing in tissue-specific and developmental-specific manner. On the other hand, cancer cells exhibit remarkable transcriptome alterations partly by adopting cancer-specific splicing isoforms. These isoforms and their encoded proteins are not insignificant byproducts of the abnormal physiology of cancer cells, but either drivers of cancer progression or small but significant contributors to specific cancer hallmarks. Thus, it is paramount that the pathways that regulate alternative splicing in cancer, including the splicing factors that bind to pre-mRNAs and modulate spliceosome recruitment. In this review, we present a few distinct cases of alternative splicing in cancer, with an emphasis on their regulation as well as their contribution to cancer cell phenotype. Several categories of splicing aberrations are highlighted, including alterations in cancer-related genes that directly affect their pre-mRNA splicing, mutations in genes encoding splicing factors or core spliceosomal subunits, and the seemingly mutation-free disruptions in the balance of the expression of RNA-binding proteins, including components of both the major (U2-dependent) and minor (U12-dependent) spliceosomes. Given that the latter two classes cause global alterations in splicing that affect a wide range of genes, it remains a challenge to identify the ones that contribute to cancer progression. These challenges necessitate a systematic approach to decipher these aberrations and their impact on cancer. Ultimately, a sufficient understanding of splicing deregulation in cancer is predicted to pave the way for novel and innovative RNA-based therapies.
Highlights
Reviewed by: Daisuke Kaida, University of Toyama, Japan Rahul N
Advances in generation sequencing technologies and genome-wide analyses have recently underscored the fact that the vast majority of multi-exon genes under normal physiology engage in alternative splicing in tissue-specific and developmental-specific manner
Reprogrammed Alternative Splicing in Cancer to become a suitable message for downstream processes such as translation of the encoded protein, the premRNA from any multi-exon gene has to undergo extensive processing to remove the introns by an extraordinary molecular machine, the spliceosome
Summary
Reviewed by: Daisuke Kaida, University of Toyama, Japan Rahul N. Several categories of splicing aberrations are highlighted, including alterations in cancer-related genes that directly affect their pre-mRNA splicing, mutations in genes encoding splicing factors or core spliceosomal subunits, and the seemingly mutation-free disruptions in the balance of the expression of RNA-binding proteins, including components of both the major (U2dependent) and minor (U12-dependent) spliceosomes Given that the latter two classes cause global alterations in splicing that affect a wide range of genes, it remains a challenge to identify the ones that contribute to cancer progression. Introns are not extra sequences that are removed by splicing, but rather have several advantages such as coupling multiple RNA processing events for higher gene expression efficiency as well as regulation and providing a checkpoint for quality control of the mRNA They allow any gene that harbor them to have a tremendous capacity for diversification through the process of alternative splicing. It is likely that the advantages of harboring introns outweigh the disadvantages as their presence in eukaryotic genomes and to some extent their position in the genes are highly conserved (Fedorov et al, 2002; Rogozin et al, 2003), in some cases between humans and the plant Arabidopsis thaliana
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