Aug 2026· Genes & Development· Vol 40, pp. 1508 - 1522· 0 citations
Medicine
TL;DR
This study instigated a gene-specific targeted strategy by unlocking the regulatory network, and designed antisense oligonucleotides (ASOs) targeting important regulatory sites, demonstrating that ASO pharmacology is an actionable strategy for clinical development, challenging the existing paradigms in SF-mutated cancers.
Abstract
Recurrent mutations in splicing factors (SFs) have been established as crucial drivers of tumorigenesis in several types of blood cancer and are 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. 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 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.
This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology.
The CRISPR strategy shows compelling evidence as a therapeutic approach targeting PE in cancer and other human diseases as well as the preferential advantages of CRISPR over the antisense technology recently developed targeting the PE of EZH2.
Aberrant alternative splicing is increasingly recognized as a fundamental driver of cancer initiation and progression. The splicing factor 3b (SF3b) complex, an essential component of the U2 small nuclear ribonucleoprotein (snRNP), plays a pivotal role in branch point sequence (BPS) recognition and in coordinating spliceosome assembly and activation. Recent advances in cryo-electron microscopy (cryo-EM) have revealed the structural plasticity of the SF3b complex, highlighting its dynamic transition between open and closed conformations that stabilize pre-mRNA substrates during the splicing cycle. Genetic and functional perturbations of SF3b, particularly recurrent mutations in its core subunit SF3B1, are frequently observed in human malignancies, most prominently in myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). These alterations reshape splice site selection, generate aberrant transcript isoforms, and reprogram cancer-relevant signaling pathways. In this review, we integrate current knowledge of the molecular architecture and regulatory dynamics of the SF3b complex with its emerging roles in cancer-associated splicing programs. We discuss the consequences of SF3b mutations and non-mutational dysregulation on transcriptome remodeling, genome stability, and tumor cell fitness, as well as the contribution of post-translational modifications of SF3b components to splicing control. Furthermore, we critically evaluate recent progress in targeting the SF3b complex, focusing on the structural basis of SF3b inhibitors, insights gained from preclinical studies, and lessons learned from early-phase clinical trials. Collectively, this review positions the SF3b complex as a disease-modifying hub at the intersection of RNA splicing and cancer biology, and highlights the opportunities and challenges associated with therapeutically targeting spliceosome components in oncology.
Shulin Li, Li-Tong Shang, Jiayi Yang et al.· Blood Advances· 0 citations
Splicing dysregulation frequently occurs in cancers, yet the functional implications of most mis-spliced genes remain elusive. Through a comprehensive pan-cancer analysis of splicing dysregulation, we identified universally mis-spliced genes in cancers and were surprised to find their significant functional enrichment in cell migration. Interestingly, the STE20-like protein kinase (SLK) gene encoding a scaffold protein showed a significant splicing shift from SLK-S to SLK-L isoforms across various cancer types. Detailed studies demonstrated this splicing shift promoted cancer metastasis in cellular and animal models. Mechanistically, RNA-binding Fox-1 Homolog 2 (RBFOX2) protein was identified as a splicing factor that regulates SLK splicing. The two isoforms interact with occludin with different affinities, contributing to their unique activities in cancer metastasis. Notably, the antisense oligonucleotides designed to suppress SLK-L splicing effectively inhibited cancer migration and invasion. Collectively, this study shows a new splicing switch with a key role in controlling cancer metastasis, shedding light on new cancer therapy via splicing manipulation.
Yang Zhao, Yue Hu, Sishi Zhang et al.· Pharmacological Research· 0 citations
A specific protein (SRSF2) acts like a rogue editor, altering the genetic instructions of another molecule (hnRNPD) and creates a “shield” (PD-L1) on the surface of the cancer cell, effectively blinding the immune system and allowing the tumor to grow unchecked.
Zhao Cheng, Lin Jiang, Ming-yang Wang et al.· Oncogene· 0 citations
Splicing factors are frequently mutated in myeloid cancers, causing splicing aberrations that derail the expression of tumor suppressor genes. In SRSF2 mutated cancers, a key oncogenic splicing event is the inclusion of a "poison" exon that introduces an early stop codon in EZH2 mRNA, causing its destabilization. In this issue of Genes & Development, Islam et al. (doi:10.1101/gad.353628.126) define how mutant SRSF2 binding to the poison exon mediates its inclusion and identify an antisense oligonucleotide that represses the exon to restore EZH2 function and rescues hematopoietic defects. Thus, targeting of poison exons, many of which show protumorigenic and antitumorigenic properties, is a promising new avenue to treat cancer.
René M. Arvola, Guramrit Singh· Genes & Development· 0 citations