Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer Journal Article
| Authors: | Blawski, R.; Vokshi, B. H.; Guo, X.; Kittane, S.; Sallaku, M.; Chen, W.; Gjyzari, M.; Cheung, T.; Zhang, Y.; Simpkins, C.; Zhou, W.; Kulick, A.; Zhao, P.; Wei, M.; Shivashankar, P.; Prioleau, T.; Razavi, P.; Koche, R.; Rebecca, V. W.; de Stanchina, E.; Castel, P.; Chan, H. M.; Scaltriti, M.; Cocco, E.; Ji, H.; Luo, M.; Toska, E. |
| Article Title: | Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer |
| 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. © 2024 The Author(s) |
| Keywords: | controlled study; treatment response; survival analysis; human cell; methylation; nonhuman; animal cell; mouse; gene; breast cancer; animal experiment; in vitro study; proteomics; protein processing; genetic transfection; xenograft; chromatin; chromatin immunoprecipitation; plasmid; immunoblotting; cell fractionation; real time polymerase chain reaction; estrogen receptor; akt; matrix assisted laser desorption ionization time of flight mass spectrometry; rna extraction; fulvestrant; endocrine therapy; rna sequence; liquid chromatography-mass spectrometry; pik3ca; chromatin regulation; pi3k pathway; crystal violet; high throughput sequencing; estrogen receptor positive breast cancer; liquid scintillation counting; sanger sequencing; human; female; article; cell growth assay; alpelisib; mtt assay; gene set enrichment analysis; organoid; mcf-7 cell line; hek293t cell line; cell proliferation assay; kmt2d; chromatin immunoprecipitation sequencing; capivasertib; cp: molecular biology; cp: cancer; smyd2 |
| Journal Title: | Cell Reports |
| Volume: | 43 |
| Issue: | 5 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2024-05-28 |
| Start Page: | 114174 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2024.114174 |
| PUBMED: | 38700982 |
| PROVIDER: | scopus |
| PMCID: | PMC11265541 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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