2. Academic Validation
  3. Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer

Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer

  • Cell Rep. 2024 May 2;43(5):114174. doi: 10.1016/j.celrep.2024.114174.
Ryan Blawski 1,  Bujamin H Vokshi 1,  Xinyu Guo 2,  Srushti Kittane 3,  Mirna Sallaku 4,  Wanlu Chen 2,  Martina Gjyzari 1,  Tony Cheung 5,  Yuhan Zhang 3,  Christopher Simpkins 1,  Weiqiang Zhou 2,  Amanda Kulick 6,  Peihua Zhao 7,  Meihan Wei 2,  Pranavkrishna Shivashankar 3,  Tatiana Prioleau 1,  Pedram Razavi 8,  Richard Koche 9,  Vito W Rebecca 3,  Elisa de Stanchina 6,  Pau Castel 10,  Ho Man Chan 5,  Maurizio Scaltriti 11,  Emiliano Cocco 12,  Hongkai Ji 2,  Minkui Luo 13,  Eneda Toska 14
Affiliations

Affiliations

  • 1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.
  • 2 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
  • 3 Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
  • 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 AstraZeneca, Waltham, MA 02451, USA.
  • 6 Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
  • 8 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 9 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 10 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.
  • 11 AstraZeneca, Gaithersburg, MD 20878, USA.
  • 12 Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
  • 13 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 14 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA. Electronic address: etoska1@jhmi.edu.
PMID: 38700982 DOI: 10.1016/j.celrep.2024.114174
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.

Keywords

AKT; CP: Cancer; CP: Molecular biology; KMT2D; PI3K pathway; SMYD2; alpelisib; breast cancer; chromatin regulation; endocrine therapy; estrogen receptor.

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