ArticleThe Journal of clinical investigation2017
Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 161 citations in OpenAlex.
- Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study.Molecular oncology · 2022Trial
- Histone modifications: mechanisms, metabolic regulation, and therapeutic targeting in cancer.Precision clinical medicine · 2026Review
- Review
- Article
- Ribosome Homeostasis Regulated by SETD2 Preserves Intestinal Epithelial Barrier.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- EpGAT: integrating epigenetics and 3D genome structure to predict alternative splicing and polyadenylation.Briefings in bioinformatics · 2026Article
- Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and attenuate cell senescence.Cell death & disease · 2026Article
- DNA, RNA, and histone methylation regulation enzymes and their crosstalk in colorectal carcinogenesis and progression: a review of molecular mechanisms, clinical implications, and future perspectives.Cellular & molecular biology letters · 2025Review
- CPZ promotes the proliferation of gastric cancer by activating the Wnt pathway through binding with DVL2.Discover oncology · 2025Article
- Emerging role of SETD2 in the development and function of immune cells.Genes & diseases · 2025Review
- The histone methyltransferase SETD2 regulates adult brain structure, connectivity and neurogenesis.Scientific reports · 2025Article
- H3K36me3 modification by SETD2 is essential for Col11a2 and Sema3e transcription to maintain dentinogenesis in mice.Development (Cambridge, England) · 2025Article
- Intron Retention and Alzheimer's Disease (AD): A Review of Regulation Genes Implicated in AD.Genes · 2025Review
- Histone lysine methyltransferases and their specific methylation marks show significant changes in mouse testes from young to older ages.Biogerontology · 2025Article
- Alternative splicing factor RAB3IP as a novel risk signature to predict the prognosis of colorectal cancer.Journal of Cancer · 2025Article
- Catalytic activity of Setd2 is essential for embryonic development in mice: establishment of a mouse model harboring patient-derived Setd2 mutation.Frontiers of medicine · 2024Article
- The epigenetic landscape in intestinal stem cells and its deregulation in colorectal cancer.Stem cells (Dayton, Ohio) · 2024Review
- Phosphorylation of caspase-8 by RSKs via organ-constrained effects controls the sensitivity to TNF-induced death.Cell death discovery · 2024Article
- A-Z of Epigenetic Readers: Targeting Alternative Splicing and Histone Modification Variants in Cancer.Cancers · 2024Review
- PHF5A promotes esophageal squamous cell carcinoma progression via stabilizing VEGFA.Biology direct · 2024Article
42 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined. Here, we found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC). SETD2 was not required for intestinal homeostasis under steady state; however, upon irradiation, genetic inactivation of Setd2 in mouse intestinal epithelium facilitated the self-renewal of intestinal stem/progenitor cells as well as tissue regeneration. Furthermore, depletion of SETD2 enhanced the susceptibility to tumorigenesis in the context of dysregulated Wnt signaling. Mechanistic characterizations indicated that SETD2 downregulation affects the alternative splicing of a subset of genes implicated in tumorigenesis. Importantly, we uncovered that SETD2 ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, which would otherwise be degraded by nonsense-mediated decay, thereby augmenting Wnt signaling. The signaling cascades mediated by SETD2 were further substantiated by a CRC patient cohort analysis. Together, our studies highlight SETD2 as an integral regulator of Wnt signaling through epigenetic regulation of RNA processing during tissue regeneration and tumorigenesis.
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Registered trials
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 OpenQuestion graph.