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Review
. 2022 Feb;113(2):373-381.
doi: 10.1111/cas.15213. Epub 2021 Nov 30.

Aberrant RNA splicing and therapeutic opportunities in cancers

Hirofumi Yamauchi  1 , Kazuki Nishimura  1 , Akihide Yoshimi  1
Affiliations
Review

Aberrant RNA splicing and therapeutic opportunities in cancers

Hirofumi Yamauchi et al. Cancer Sci. 2022 Feb.

Abstract

There has been accumulating evidence that RNA splicing is frequently dysregulated in a variety of cancers and that hotspot mutations affecting key splicing factors, SF3B1, SRSF2 and U2AF1, are commonly enriched across cancers, strongly suggesting that aberrant RNA splicing is a new class of hallmark that contributes to the initiation and/or maintenance of cancers. In parallel, some studies have demonstrated that cancer cells with global splicing alterations are dependent on the transcriptional products derived from wild-type spliceosome for their survival, which potentially creates a therapeutic vulnerability in cancers with a mutant spliceosome. It has been c. 10 y since the frequent mutations affecting splicing factors were reported in cancers. Based on these surprising findings, there has been a growing interest in targeting altered splicing in the treatment of cancers, which has promoted a wide variety of investigations including genetic, molecular and biological studies addressing how altered splicing promotes oncogenesis and how cancers bearing alterations in splicing can be targeted therapeutically. In this mini-review we present a concise trajectory of what has been elucidated regarding the pathogenesis of cancers with aberrant splicing, as well as the development of therapeutic strategies to target global splicing alterations in cancers.

Keywords: RNA binding protein; SF3b; antisense oligonucleotide; cancer; splicing factor.

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Figures

FIGURE 1
FIGURE 1
Mutational hotspots in genes encoding the major splicing factors. Frequent somatic mutations in SF3B1 (A), SRSF2 (B) and U2AF1 (C). The numbers in the center of the flame icon represent the percentage of samples with indicated mutations within “hotspot” mutations that were previously demonstrated to be pathogenic. These pan‐cancer samples with spliceosome mutations were collected from Columbia University Medical Center, Memorial Sloan Kettering Cancer Center, and public portal resources including TCGA, the ICGC database of Genotypes and Phenotypes (dbGaP), and the Gene Expression Omnibus (GEO), as previously described. RRM, RNA recognition motif; RS domain, arginine/serine‐rich domain; ZnF, zinc finger; UHM, U2AF homology motif
FIGURE 2
FIGURE 2
Splicing catalysis, the spliceosome assembly pathway, and mechanisms of splice site selection. A, Diagram of an intron, 2 flanking exons, U1 and U2 snRNP, associated RNA binding proteins, and U2 snRNA, and the sequential reactions involved in removal of an intron. The U2 snRNP complex and U2AF complex recognize the BPS and 3′ss, respectively, which is an essential step for removing introns from pre‐mRNA. Accessory splicing regulatory proteins are also involved in splicing. B, Classification of alternative RNA splicing
FIGURE 3
FIGURE 3
Functional consequences of SF3B1, SRSF2, and U2AF1 mutations in RNA splicing. A, Description of canonical splicing. B, Mutations in SF3B1 (marked in red) result in enhanced usage of an aberrant branchpoint to generate an alternative 3′ss. C, Mutations in SRSF2 are clustered at the proline 95 residue and alter the preference of ESE motif recognition. D, U2AF1 mutations alter the 3′ss consensus sequences. U2AF1 S34F/Y mutations favor inclusion of cassette exons with a C‐nucleotide at the “−3” position, whereas U2AF1 Q157P/R mutations favor inclusion of cassette exons with a G‐nucleotides at the “+1” position
FIGURE 4
FIGURE 4
Strategies for targeting splicing alterations in cancers. A, The U2 snRNP inhibitor disrupts U2 snRNP’s ability to recognize the branchpoint region of the intron. B, Sulfonamide compounds physically link RBM39 to the CUL4‐DCAF15 ubiquitin ligase, resulting in ubiquitination of RBM39 and subsequent proteasomal degradation. C, CLK, SRPK, and PRMT inhibitors are promising because the function, cellular localization, and assembly of a variety of splicing proteins depend on post–translational modifications. D, Antisense oligonucleotides modify splicing of specific transcripts by blocking the RNA‐RNA base pairing or protein‐RNA binding interactions
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