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Updated: May 11, 2026
Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Targeting EZH2 Oncogenic Splicing: Decoding the Regulatory Network and Antisense Correction
Abstract:
Recurrent mutations in splicing factors (SFs) have been established as crucial drivers of tumorigenesis in several types of blood cancer, and also common in a variety of solid tumors. Mutations change the RNA-binding preferences of SFs, promote global splicing alterations, and often generate erroneous mRNAs that are then degraded by nonsense-mediated mRNA decay (NMD). Consequently, several critical genes linked to hematopoiesis are dysregulated, leading to blood cancer. Although the field has progressed considerably in identifying aberrant genes and affected pathways, effective therapies have not yet emerged in SF-mutated cancers. To address this key gap, we instigated a gene-specific targeted strategy by unlocking the regulatory network. As a proof-of-concept, we scrutinized a tumor suppressor gene EZH2 , which is a bona fide target in SRSF2-mutated cancer. We precisely defined splicing cis-elements in EZH2 transcripts and illustrated the dynamic choreography of regulatory proteins in the entire splicing and NMD catalytic pathways. We uncovered a highly coordinated cross-regulation between splicing and NMD promoted by mutant SRSF2 by enhancing the deposition of critical spliceosome- and NMD-associated factors, augmenting mRNA decay to ablate tumor suppression. We then designed antisense oligonucleotides (ASOs) targeting important regulatory sites. Our lead ASO successfully corrects aberrant splicing and NMD, restores the expression and function of EZH2, and partially rescues hematopoietic defects and cellular properties. Our study demonstrates that ASO pharmacology is an actionable strategy for clinical development, challenging the existing paradigms in SF-mutated cancers.
Insights
Mutations in splicing factors (SFs) drive cancer by altering RNA splicing and mRNA decay. This study shows antisense oligonucleotides (ASOs) can correct these defects, restoring tumor suppressor function and offering a new therapeutic strategy for SF-mutated cancers.
Area of Science:
- Molecular Biology
- Cancer Genetics
- RNA Biology
Background:
- Recurrent mutations in splicing factors (SFs) are key drivers in blood and solid tumors.
- SF mutations alter RNA binding, leading to global splicing changes and mRNA decay via nonsense-mediated mRNA decay (NMD).
- Dysregulation of critical genes, particularly in hematopoiesis, contributes to cancer development, yet effective therapies for SF-mutated cancers are lacking.
Purpose of the Study:
- To investigate the regulatory network disrupted by SF mutations.
- To develop a gene-specific targeted therapy for SF-mutated cancers.
- To demonstrate the therapeutic potential of antisense oligonucleotides (ASOs) in correcting aberrant splicing and NMD.
Main Methods:
- Detailed analysis of splicing cis-elements and regulatory protein interactions in EZH2 transcripts.
- Investigation of the cross-regulation between splicing and NMD pathways in SRSF2-mutated cancer models.
- Design and testing of ASOs targeting key regulatory sites to correct splicing and NMD defects.
Main Results:
- Mutant SRSF2 was found to enhance spliceosome and NMD factor deposition, increasing mRNA decay and suppressing tumor suppressors like EZH2.
- A lead ASO was developed that successfully corrected aberrant splicing and NMD.
- The ASO restored EZH2 expression and function, partially rescuing hematopoietic defects and cellular properties.
Conclusions:
- ASO pharmacology represents a viable and actionable therapeutic strategy for SF-mutated cancers.
- This approach challenges existing treatment paradigms by targeting the root cause of SF-driven tumorigenesis.
- The study provides a proof-of-concept for developing targeted therapies based on understanding SF mutation-induced regulatory networks.
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