Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome

Abstract

Over the past decade there has been increased awareness of the potential role of alternative splicing in the etiology of cancer. In particular, advances in RNA-Sequencing technology and analysis has led to a wave of discoveries in the last few years regarding the causes and functional relevance of alternative splicing in cancer. Here we discuss the current understanding of the connections between splicing and cancer, with a focus on the most recent findings. We also discuss remaining questions and challenges that must be addressed in order to use our knowledge of splicing to guide the diagnosis and treatment of cancer.

Keywords: alternative splicing; cancer; transcriptomic analysis.

Figure 1.

Common patterns of AS. Rectangles represent exons and lines represent introns. Dotted lines connect exons that are joined together to form the final mRNA. Red and blue regions are those that can be differentially included in the mature mRNA. Dotted lines above and below represent the two alternate possible splicing patterns.

Figure 2.

General mechanism of splicing and its regulation. (A) Spliceosome assembly. The 5′ end of introns are defined by the 5′ splice site (GU) and the 3′ end of introns are defined by the branch point sequence (BPS), polypyrimidine tract (PPT), and the 3′ splice site AG dinucleotides. The U1, U2, U4, U5, and U6 represent the snRNPs that assemble with substrate and each other as shown. The NTC is an additional snRNA-free spliceosomal subunit. The U2AF heterodimeric complex of a 65- and 35-kDa subunit, and the SF1 protein, recognize the 3′ endo of the intron prior to recruitment of the U2snRNP. SF3B1 is a component of the U2snRNP that makes direct contact with the substrate. (B) Regulation of alternative splicing. Enhancer auxiliary elements are denoted in green for exonic (ESE) or intronic (ISE) splicing enhancers. Silencer auxiliary elements are denoted in red for exonic (ESS) or intronic (ISS) splicing silencers. The activities of these auxiliary elements are often mediated through binding of SR and hnRNPs, two common families of RNA-binding proteins described in the text and Figure 3.

Figure 3.

Common splicing regulatory RNA-binding proteins. Domain schematics for each factor are displayed. (RRM) RNA recognition motif; (psRRM) pseudo-RRM; (RS) arginine/serine-rich; (Zn) zinc finger; (Gly) glycine-rich region; (P) proline-rich region; (RGG) arginine/glycine/glycine repeat region; (RS) arginine/serine-rich; (KH) K homology domain. Binding preferences for each factor are specified for SRSF1 (Ray et al. 2013), SRSF2 (Kim et al. 2015; Zhang et al. 2015), SRSF7 (Ray et al. 2013), hnRNP A1 (Ray et al. 2013), PTB (Xue et al. 2009), hnRNP L (Hui et al. 2005), and hnRNP K (Klimek-Tomczak et al. 2004).