ArticlePLoS biology2021
Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 34 citations in OpenAlex.
- An in vivo parallelized reporter assay to uncover tissue-specific splicing regulatory sequences in a multicellular animal.Nucleic acids research · 2026Article
- Exon inclusion signatures enable accurate estimation of splicing factor activity.Nature communications · 2026Article
- SRRM4 Knockout Helps the Human Mesenchymal Stem Cell Line to Penetrate Decellularized Cancellous Bone.Bioengineering (Basel, Switzerland) · 2025Article
- Molecular mechanisms by which C1orf112 promotes endometrial cancer progression and the development and validation of a clinical scoring model.Clinical epigenetics · 2025Article
- Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4.Nature structural & molecular biology · 2025Article
- NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas.Cell reports · 2025Article
- Exon inclusion signatures enable accurate estimation of splicing factor activity.bioRxiv : the preprint server for biology · 2025Article
- Steering research on mRNA splicing in cancer towards clinical translation.Nature reviews. Cancer · 2024Review
- Circular RNA in cancer.Nature reviews. Cancer · 2024Review
- In silico RNA isoform screening to identify potential cancer driver exons with therapeutic applications.Nature communications · 2024Article
- Characterization of RNA Processing Genes in Colon Cancer for Predicting Clinical Outcomes.Biomarker insights · 2024Article
- High frequency of alternative splicing variants of the oncogene Focal Adhesion Kinase in neuroendocrine tumors of the pancreas and breast.Frontiers of medicine · 2023Article
- Insplico: effective computational tool for studying splicing order of adjacent introns genome-wide with short and long RNA-seq reads.Nucleic acids research · 2023Article
- Exon definitive regions forMolecular therapy. Nucleic acids · 2023Article
- An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells.Cancer cell international · 2023Article
- Editorial: RNA machines.Frontiers in genetics · 2023Article
- Specialization of the photoreceptor transcriptome byProceedings of the National Academy of Sciences of the United States of America · 2022Article
- The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians.PLoS biology · 2022Article
- Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer.International journal of molecular sciences · 2022Review
- Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals.Science advances · 2022Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3-27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.