SMYD5 methylation of rpL40 links ribosomal output to gastric cancer

Nature. 2024 Aug;632(8025):656-663. doi: 10.1038/s41586-024-07718-0. Epub 2024 Jul 24.

Abstract

Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Disease Progression
  • Epigenesis, Genetic / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation / drug effects
  • Methyltransferases* / antagonists & inhibitors
  • Methyltransferases* / deficiency
  • Methyltransferases* / metabolism
  • Mice
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Protein Biosynthesis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribosomal Proteins* / chemistry
  • Ribosomal Proteins* / metabolism
  • Ribosomes* / metabolism
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Histone-Lysine N-Methyltransferase
  • Lysine
  • Methyltransferases
  • MTOR protein, human
  • Phosphatidylinositol 3-Kinases
  • Phosphoinositide-3 Kinase Inhibitors
  • Ribosomal Proteins
  • RNA, Messenger
  • SMYD5 protein, human
  • TOR Serine-Threonine Kinases
  • UBA52 protein, human