SMYD5 methylation of rpL40 links ribosomal output to gastric cancer

Juhyung Park, Jibo Wu, Krzysztof J. Szkop, Jinho Jeong, Predrag Jovanovic, Dylan Husmann, Natasha M. Flores, Joel W. Francis, Ying-Jiun C. Chen, Ana Morales Benitez, Emily Zahn, Shumei Song, Jaffer A. Ajani, Linghua Wang, Kamini Singh, Ola Larsson, Benjamin A. Garcia, Ivan Topisirovic, Or Gozani () and Pawel K. Mazur ()
Additional contact information
Juhyung Park: Stanford University
Jibo Wu: The University of Texas MD Anderson Cancer Center
Krzysztof J. Szkop: Karolinska Institute
Jinho Jeong: Stanford University
Predrag Jovanovic: McGill University
Dylan Husmann: Stanford University
Natasha M. Flores: The University of Texas MD Anderson Cancer Center
Joel W. Francis: Stanford University
Ying-Jiun C. Chen: Stanford University
Ana Morales Benitez: The University of Texas MD Anderson Cancer Center
Emily Zahn: Washington University School of Medicine
Shumei Song: The University of Texas MD Anderson Cancer Center
Jaffer A. Ajani: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Kamini Singh: Montefiore Einstein Cancer Center
Ola Larsson: Karolinska Institute
Benjamin A. Garcia: Washington University School of Medicine
Ivan Topisirovic: McGill University
Or Gozani: Stanford University
Pawel K. Mazur: The University of Texas MD Anderson Cancer Center

Nature, 2024, vol. 632, issue 8025, 656-663

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07718-0

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