ArticleAging2020
High expression of SMYD3 indicates poor survival outcome and promotes tumour progression through an IGF-1R/AKT/E2F-1 positive feedback loop in bladder cancer.
Article in Aging, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 32 citations in OpenAlex.
- A novel molecule ZYZ329 targeting histone methyltransferase SMYD3 suppresses pathological angiogenesis via the driven mitochondrial ROS/HIF-1α/VEGFA axis.Journal of translational medicine · 2026Article
- NCAPD2 promotes the progression of lung adenocarcinoma through an AKT/MDM2/E2F1 positive feedback loop.Cancer biology & therapy · 2025Article
- Downregulation of HDGF inhibits tumorigenic phenotypes of hypopharyngeal squamous cell carcinoma by suppressing the AKT/mTOR/VEGF pathway.Frontiers in oncology · 2025Article
- SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance.Experimental & molecular medicine · 2024Review
- The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer.Science advances · 2023Article
- SMYD3 drives the proliferation in gastric cancer cells via reducing EMP1 expression in an H4K20me3-dependent manner.Cell death & disease · 2023Article
- SMYD Family Members Serve as Potential Prognostic Markers and Correlate with Immune Infiltrates in Gastric Cancer.Journal of oncology · 2023Article
- Article
- SMYD3: a regulator of epigenetic and signaling pathways in cancer.Clinical epigenetics · 2021Review
- Epigenetic Regulation of Hepatocellular Carcinoma Progression through the mTOR Signaling Pathway.Canadian journal of gastroenterology & hepatology · 2021Review
- VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR.Oncogene · 2020Article
- Article
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Authors and funding
18 authors at 10 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The AKT/mTOR pathway is critical for bladder cancer (BC) pathogenesis and is hyper-activated during BC progression. In the present study, we identified a novel positive feedback loop involving oncogenic factors histone methyltransferase SMYD3, insulin-like growth factor-1 receptor (IGF-1R), AKT, and E2F-1. SMYD3 expression was significantly up-regulated in BC tumors and positively associated with histological grade, lymph node metastasis, and shorter patient survival. Depletion of SMYD3 inhibited BC cell proliferation, colony formation, migration, invasion, and xenograft tumor growth. Mechanistically, SMYD3 inhibition led to the diminished AKT/mTOR signaling activity, thereby triggering deleterious effects on BC cells. Furthermore, SMYD3 directly activates the expression of IGF-1R, a critical activator of AKT in BC, by inducing hyper-methylation of histone H3-K4 and subsequent chromatin remodeling in the IGF-1R promoter region. On the other hand, E2F-1, a downstream factor of the AKT pathway, binds to the E2F-1 binding motifs at the SMYD3 promoter and consequently induces SMYD3 transcription and expression. Thus, SMYD3/IGF-1R/AKT/E2F-1 forms a positive feedback loop leading to the hyper-activated AKT signaling. Our findings provide not only profound insights into SMYD3-mediated oncogenic activity but also present a unique avenue for treating BC by directly disrupting this signaling circuit.
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