ArticleJournal of experimental & clinical cancer research : CR2024
The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- DDX21 Enhances Radiosensitivity in Head and Neck Squamous Cell Carcinoma by Suppressing MK2-Mediated DNA Damage Response.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting the DNA-repair chromatin-modifier protein SMYD3 as a novel epigenetics-based therapy for gastric cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- 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
- Translational Aspects of DNA Damage Repair in Optimizing Cancer Chemotherapy.Advanced genetics (Hoboken, N.J.) · 2025Review
- SMYD3-CDCP1 Axis Drives EMT and CAF Activation in Colorectal Cancer and Is Targetable for Oxaliplatin Sensitization.Biomedicines · 2025Article
- Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis.Signal transduction and targeted therapy · 2025Article
- TTI1 contributes to radioresistance by activating ATM pathway in rectal cancer.Journal of translational medicine · 2025Article
- Insights into the DNA damage response and tumor drug resistance.Cancer biology & medicine · 2025Article
- Lysine Methyltransferases SMYD2 and SMYD3: Emerging Targets in Kidney Diseases.Kidney diseases (Basel, Switzerland)Review
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26 authors.
Funding
Abstract
backgroundSMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair.
methodsIn cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients' residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs).
resultsHere we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models.
conclusionsOverall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.
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