RNA splicing dysregulation and the hallmarks of cancer.
RNA splicing dysregulation and the hallmarks of cancer. Nat Rev Cancer. 2023;23:135-55.
JGM, Humans, Alternative Splicing, RNA Splicing, Neoplasms, Protein Isoforms, Carcinogenesis, Cell Transformation, Neoplastic
Nat Rev Cancer. 2023;23:135-55.
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.
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.