1. Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.
- Author
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Blawski R, Vokshi BH, 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 VW, de Stanchina E, Castel P, Chan HM, Scaltriti M, Cocco E, Ji H, Luo M, and Toska E
- Subjects
- Humans, Female, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics, Methylation drug effects, Cell Line, Tumor, Animals, Mice, Proto-Oncogene Proteins c-akt metabolism, Neoplasm Proteins metabolism, Neoplasm Proteins genetics, Receptors, Estrogen metabolism, Gene Expression Regulation, Neoplastic drug effects, Histone-Lysine N-Methyltransferase metabolism, Histone-Lysine N-Methyltransferase genetics, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Chromatin metabolism
- 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., Competing Interests: Declaration of interests M. Sallaku is an employee of Loxo Oncology. M. Scaltriti has ownership interest (including patents) in Medendi.org, reports other support from AstraZeneca, and is an employee of AstraZeneca. H.M.C. and T.C. are employees of AstraZeneca. P.C. reports personal fees from Venthera outside the submitted work. P.R. has received institutional grants/funding from Grail, Novartis, AstraZeneca, EpicSciences, Invitae/ArcherDx, Biothernostics, Tempus, Neogenomics, Biovica, Guardant, Personalis, and Myriad and has shares/ownership interest in Odyssey Biosciences as well as consultation/ad-board/honoraria from Novartis, AstraZeneca, Pfizer, Lilly/Loxo, Prelude Therapeutics, Epic Sciences, Daiichi-Sankyo, Foundation Medicine, Inivata, Tempus, SAGA Diagnostics, Paige.ai, Guardant, and Myriad. E.T. reports grants and personal fees from AstraZeneca and consulting from Menarini., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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