Splicing factors: Insights into their regulatory network in alternative splicing in cancer

• Published in: Cancer letters Vol. 501; pp. 83 - 104
• Main Authors: Du, Jun-Xian, Zhu, Gui-Qi, Cai, Jia-Liang, Wang, Biao, Luo, Yi-Hong, Chen, Cong, Cai, Cheng-Zhe, Zhang, Si-Jia, Zhou, Jian, Fan, Jia, Zhu, Wei, Dai, Zhi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 31.03.2021; Elsevier Limited
• Subjects: Alternative splicing; Angiogenesis; Apoptosis; Cancer; Cell growth; Cooperation; Hallmarks of cancer; Isoforms; Kinases; Localization; Metastases; Oligonucleotides; Post-transcriptional modification; Proteins; siRNA; Spliceosomes; Splicing factors; Therapeutic targets; Transcription; Transcriptional modification; Alternative splicing; Hallmarks of cancer; Splicing factors; Post-transcriptional modification; Transcriptional modification; Therapeutic targets
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.11.043

More than 95% of all human genes are alternatively spliced after transcription, which enriches the diversity of proteins and regulates transcript and/or protein levels. The splicing isoforms produced from the same gene can manifest distinctly, even exerting opposite effects. Mounting evidence indicates that the alternative splicing (AS) mechanism is ubiquitous in various cancers and drives the generation and maintenance of various hallmarks of cancer, such as enhanced proliferation, inhibited apoptosis, invasion and metastasis, and angiogenesis. Splicing factors (SFs) play pivotal roles in the recognition of splice sites and the assembly of spliceosomes during AS. In this review, we mainly discuss the similarities and differences of SF domains, the details of SF function in AS, the effect of SF-driven pathological AS on different hallmarks of cancer, and the main drivers of SF expression level and subcellular localization. In addition, we briefly introduce the application prospects of targeted therapeutic strategies, including small-molecule inhibitors, siRNAs and splice-switching oligonucleotides (SSOs), from three perspectives (drivers, SFs and pathological AS). Finally, we share our insights into the potential direction of research on SF-centric AS-related regulatory networks. •More than 95% of all human genes are alternatively spliced after transcription. Notably, it also affects the regulation of noncoding RNAs.•The spliceosome complex catalyzing the constitutive and alternative splicing (AS) process include more than 100 trans-acting factors, among which heterogeneous nuclear ribonucleoproteins (hnRNPs) and Ser/Arg-rich (SR) proteins belong to well-established splicing factor (SF) families.•Aberrant AS mediated by disturbance to SF function is associated with numerous human diseases, including cancer.•The pivotal drivers affects the expression levels or AS activities of SFs at the transcriptional and posttranscriptional levels.•Snap shot of representative strategies including small-molecule inhibitors, siRNA and splice-switching oligonucleotides (SSOs) that target key drivers, SFs or dysregulated AS components.