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) drive tumorigenesis in blood and solid cancers.
• SF mutations alter RNA binding, cause splicing errors, and trigger nonsense-mediated mRNA decay (NMD), dysregulating critical genes like those in hematopoiesis.
• Current therapies for SF-mutated cancers are limited despite advances in identifying affected genes and pathways.

Purpose of the Study:

• To develop a gene-specific targeted therapy for SF-mutated cancers.
• To demonstrate the potential of antisense oligonucleotide (ASO) pharmacology as a clinical strategy.

Main Methods:

• Investigated the tumor suppressor gene EZH2 as a target in SRSF2-mutated cancer.
• Defined splicing cis-elements and mapped regulatory proteins in splicing and NMD pathways for EZH2.
• Designed and tested ASOs targeting key regulatory sites on EZH2 transcripts.

Main Results:

• The lead ASO effectively corrected aberrant splicing and NMD.
• Restored EZH2 expression and function, partially rescuing hematopoietic defects and cellular properties.
• Demonstrated ASO pharmacology as a viable therapeutic approach.

Conclusions:

• ASO-based therapy is an actionable strategy for clinical development in SF-mutated cancers.
• This approach challenges existing treatment paradigms for these cancers.