ArticleNucleic acids research2018
Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 63 citations in OpenAlex.
- Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome.Scientific reports · 2020Trial
- Bioinformatics analysis and differential tissue expression of the IGFBP4 gene in beef cattle.Protoplasma · 2026Article
- Crosstalk BetweenCancers · 2026Review
- Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- GATOR1 complex controls cisplatin sensitivity.Cell death & disease · 2025Article
- AI-aided identification of dual-purpose therapeutic targets PRPF19 and MAPK9 in hepatocellular carcinoma and cellular senescence.npj aging · 2025Article
- The LUBAC subunit HOIL-1 promotes the progression of HBV-associated hepatocellular carcinoma independently of linear ubiquitination.Experimental & molecular medicine · 2025Article
- Pantothenic acid ameliorates hepatic fibrosis by targeting IGFBP6 to regulate the TGF-β/SMADs pathway.Communications biology · 2025Article
- Human placenta mesenchymal stromal cells alleviate intestinal inflammation and repair intestinal barrier function by activating AMPK-FXR pathway.Communications biology · 2025Article
- Diffusion-based generation of gene regulatory networks from scRNA-seq data with DigNet.Genome research · 2025Article
- Alternative splicing of EZH2 regulated by SNRPB mediates hepatocellular carcinoma progression via BMP2 signaling pathway.iScience · 2025Article
- Insulin-like growth factor family and its impact on pulmonary arterial hypertension: a review.Frontiers in physiology · 2025Review
- KLF9 in cancer: a potential prognostic marker and therapeutic target.Frontiers in oncology · 2025Review
- MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer.International journal of oncology · 2025Article
- Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma.Cell death & disease · 2024Article
- MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data.Nature communications · 2024Article
- Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis.BMC genomics · 2024Article
- Activation of IGFBP4 via unconventional mechanism of miRNA attenuates metastasis of intrahepatic cholangiocarcinoma.Hepatology international · 2024Article
- The RNA binding protein MEX3A promotes tumor progression of breast cancer by post-transcriptional regulation of IGFBP4.Breast cancer research and treatment · 2023Article
- mCell biology and toxicology · 2023Article
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Authors and funding
20 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.
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