SMYD5 regulates mRNA translation to promote gastric adenocarcinoma (GAC)
Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis. 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 at lysine 22 (rpL40K22me3) by the lysine methyltransferase (KMT) SMYD5 regulates mRNA translation output to promote gastric adenocarcinoma (GAC) malignant progression with lethal peritoneal ascites. A biochemical-proteomic strategy identifies the mono-ubiquitin fusion protein partner rpL40 as the principal physiologic substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprograms protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in GAC patient samples 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 (PC). Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to PI3K/mTOR inhibitors. Finally, combining SMYD5 depletion with PI3K/mTOR inhibition and CAR-T administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived PC. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates evolution of malignant GAC and nominates SMYD5 targeting as part of a potential cornerstone combination therapy to treat a deadly cancer. Overall design: Analysis of total and polysome-associated RNA-sequencing of Control and SMYD5 knockout samples (3 vs 3)