Targeting EZH2 Oncogenic Splicing: Decoding the Regulatory Network and Antisense Correction.

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.