Abstract
Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing’s contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.
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Acknowledgements
The authors thank members of the Bradley and Anczukow laboratories for helpful discussions. O.A. was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) (R01 CA248317 and P30 CA034196) and NIH/National Institute of General Medical Sciences (NIGMS) (R01 GM138541). R.K.B. was supported, in part, by the NIH/NCI (R01 CA251138), NIH/National Heart, Lung, and Blood Institute (NHLBI) (R01 HL128239 and R01 HL151651) and the Blood Cancer Discoveries Grant programme through the Leukaemia & Lymphoma Society, Mark Foundation for Cancer Research and Paul G. Allen Frontiers Group (8023-20). R.K.B. is a Scholar of The Leukaemia & Lymphoma Society (1344-18) and holds the McIlwain Family Endowed Chair in Data Science.
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R.K.B. is an inventor on patent applications filed by Fred Hutchinson Cancer Center related to modulating splicing for cancer therapy. O.A. is an inventor on a patent application filed by The Jackson Laboratory related to modulating splicing factors.
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Glossary
- Branch point
-
A nucleotide that performs a nucleophilic attack on the 5′ splice site (5′SS) in the first step of splicing.
- K homology (KH) domain
-
A protein domain that can bind RNA and is found in various RNA-binding proteins (RBPs), including splicing factors.
- Polypyrimidine tract
-
A pyrimidine (C or T)-rich sequence motif upstream of many 3′ splice sites (3′SSs) that is bound by the U2AF2 subunit of the U2AF heterodimer to facilitate 3′SS recognition.
- RNA splicing
-
A post-transcriptional mechanism that mediates the removal of introns from a pre-mRNA transcript and the ligation of exons to form a mature mRNA.
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Bradley, R.K., Anczuków, O. RNA splicing dysregulation and the hallmarks of cancer. Nat Rev Cancer 23, 135–155 (2023). https://doi.org/10.1038/s41568-022-00541-7
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DOI: https://doi.org/10.1038/s41568-022-00541-7
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