Juhyung Park

All Publications

• SMYD5 methylation of rpL40 links ribosomal output to gastric cancer. Nature Park, J., Wu, J., Szkop, K. J., Jeong, J., Jovanovic, P., Husmann, D., Flores, N. M., Francis, J. W., Chen, Y. C., Benitez, A. M., Zahn, E., Song, S., Ajani, J. A., Wang, L., Singh, K., Larsson, O., Garcia, B. A., Topisirovic, I., Gozani, O., Mazur, P. K. 2024

  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 Tcell 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.

  View details for DOI 10.1038/s41586-024-07718-0

  View details for PubMedID 39048817

• Antibody toolkit to investigate eEF1A methylation dynamics in mRNA translation elongation. The Journal of biological chemistry Mealey-Farr, R., Jeong, J., Park, J., Liu, S., Hausmann, S., Francis, J. W., Angulo Ibanez, M., Cho, J., Chua, K., Mazur, P. K., Gozani, O. 2023: 104747

  Abstract

  Protein synthesis is a fundamental step in gene expression, with modulation of mRNA translation at the elongation step emerging as an important regulatory node in shaping cellular proteomes. In this context, five distinct lysine methylation events on eEF1A (eukaryotic elongation factor 1A), a fundamental non-ribosomal elongation factor, are proposed to influence mRNA translation elongation dynamics. However, a lack of affinity tools has hindered progress in fully understanding how eEF1A lysine methylation impacts protein synthesis. Here we develop and characterize a suite of selective antibodies to investigate eEF1A methylation and provide evidence that methylation levels decline in aged tissue. Determination of the methyl state and stoichiometry on eEF1A in various cell lines by mass spectrometry shows modest cell-to-cell variability. We also find by Western blot analysis that knockdown of individual eEF1A-specific lysine methyltransferases (KMTs) leads to depletion of the cognate lysine methylation event and indicates active crosstalk between different sites. Further, we find that the antibodies are specific in immunohistochemistry (IHC) applications. Finally, application of the antibody toolkit suggests that several eEF1A methylation events decrease in aged muscle tissue. Together our study provides a roadmap for leveraging methyl state and sequence selective antibody reagents to accelerate discovery of eEF1A methylation-related functions and suggests a role for eEF1A methylation, via protein synthesis regulation, in aging biology.

  View details for DOI 10.1016/j.jbc.2023.104747

  View details for PubMedID 37094697