한빛사논문
- 조회482
Juhyung Park 1,10, Jibo Wu 2,10, Krzysztof J. Szkop 3, Jinho Jeong 1, Predrag Jovanovic 4, Dylan Husmann 1, Natasha M. Flores 2, Joel W. Francis 1, Ying-Jiun C. Chen 1,9, Ana Morales Benitez 2, Emily Zahn 5, Shumei Song 6, Jaffer A. Ajani 6, Linghua Wang 7, Kamini Singh 8, Ola Larsson 3, Benjamin A. Garcia 5, Ivan Topisirovic 4, Or Gozani 1,* & Pawel K. Mazur 2,*
1Department of Biology, Stanford University, Stanford, CA, USA.
2Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3Department of Oncology–Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden.
4Lady Davis Institute and Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.
5Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA.
6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8Department of Molecular Pharmacology, Albert Einstein College of Medicine, Montefiore Einstein Cancer Center, Bronx, NY, USA.
9Present address: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10These authors contributed equally: Juhyung Park, Jibo Wu.
*Corresponding authors: correspondence to Or Gozani or Pawel K. Mazur
Abstract
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 (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.) 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.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-30)
- 국외 연구진
- 생명과학 > 노화/암생물학
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