ArticleCell reports2024
Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.
Article in Cell reports, 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.
- Targeting the Chromatin-Modifying Enzyme, KDM5C, Enhances AKT Inhibition Response in ER+ Breast Cancer.Molecular cancer therapeutics · 2026Article
- Enhancer-mediated DDIT4 activation by SMYD2-dependent H3K4me1 promotes pazopanib resistance in clear cell renal cell carcinoma.Journal of translational medicine · 2026Article
- Sublytic C5b-9 induces S100A8/A9 expression via SMYD4-dependent SOX7-K159 methylation in the glomerular mesangial cells of Thy-1 nephritis rats.Journal of molecular cell biology · 2026Article
- Nucleic sexual hormone receptor signaling pathways in breast cancer: function regulation, crosstalk, and therapeutic implications.NPJ precision oncology · 2026Review
- The Histone Methyltransferase KMT2D Is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration-Resistant Prostate Cancer.Cancer research · 2026Article
- Using transfer learning approaches to predict RNA-Seq gene expression data for cancer classification.Frontiers in artificial intelligence · 2026Article
- Harnessing Nature's Chemistry: Deciphering Olive Oil Phenolics for the Control of Invasive Breast Carcinoma.Molecules (Basel, Switzerland) · 2025Article
- Epigenetic regulation of nuclear receptors: Implications for endocrine-related diseases and therapeutic strategies.Genes & diseases · 2025Review
- Class III Phosphatidylinositol-3 Kinase/Vacuolar Protein Sorting 34 in Cardiovascular Health and Disease.Journal of cardiovascular translational research · 2025Review
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Authors and funding
27 authors.
Funding
Abstract
Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.
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