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
  • 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: [email protected].
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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