Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics.
Document Type
Article
Publication Date
7-2018
JAX Source
Wiley Interdiscip Rev RNA 2018 Jul; 9(4):e1476
Volume
9
Issue
4
First Page
1476
Last Page
1476
ISSN
1757-7012
PMID
29693319
DOI
https://doi.org/10.1002/wrna.1476
Grant
CA178206, The Jackson Laboratory
Abstract
Defects in alternative splicing are frequently found in human tumors and result either from mutations in splicing-regulatory elements of specific cancer genes or from changes in the regulatory splicing machinery. RNA splicing regulators have emerged as a new class of oncoproteins and tumor suppressors, and contribute to disease progression by modulating RNA isoforms involved in the hallmark cancer pathways. Thus, dysregulation of alternative RNA splicing is fundamental to cancer and provides a potentially rich source of novel therapeutic targets. Here, we review the alterations in splicing regulatory factors detected in human tumors, as well as the resulting alternatively spliced isoforms that impact cancer hallmarks, and discuss how they contribute to disease pathogenesis. RNA splicing is a highly regulated process and, as such, the regulators are themselves tightly regulated. Differential transcriptional and posttranscriptional regulation of splicing factors modulates their levels and activities in tumor cells. Furthermore, the composition of the tumor microenvironment can also influence which isoforms are expressed in a given cell type and impact drug responses. Finally, we summarize current efforts in targeting alternative splicing, including global splicing inhibition using small molecules blocking the spliceosome or splicing-factor-modifying enzymes, as well as splice-switching RNA-based therapeutics to modulate cancer-specific splicing isoforms. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing.
Recommended Citation
Urbanski L,
Leclair N,
Anczuków O.
Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip Rev RNA 2018 Jul; 9(4):e1476
Comments
We thank Stephen Sampson and Juergen Scharner for reading and editing the manuscript and Matt Wimsatt for assistance with graphical art in Figure 1.