2. Academic Validation
  3. SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma

SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma

  • Cell Res. 2024 Aug 5. doi: 10.1038/s41422-024-01013-3.
Bisi Miao # 1,  Ling Ge # 1,  Chenxi He # 1,  Xinghao Wang # 2,  Jibo Wu # 3,  Xiang Li 4,  Kun Chen 1,  Jinkai Wan 1,  Shenghui Xing 1,  Lingnan Ren 1,  Zhennan Shi 1,  Shengnan Liu 2,  Yajun Hu 1,  Jiajia Chen 1,  Yanyan Yu 2,  Lijian Feng 2,  Natasha M Flores 3,  Zhihui Liang 1,  Xinyi Xu 1,  Ruoxin Wang 1,  Jian Zhou 1,  Jia Fan 1,  Bin Xiang 2,  En Li 2,  Yuanhui Mao 5,  Jingdong Cheng 4,  Kehao Zhao 2,  Pawel K Mazur 6,  Jiabin Cai 7,  Fei Lan 8
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 China Novartis Institutes for BioMedical Research, Shanghai, China.
  • 3 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China.
  • 5 Department of Neurology of The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 6 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. pkmazur@mdanderson.org.
  • 7 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. cai.jiabin@zs-hospital.sh.cn.
  • 8 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. fei_lan@fudan.edu.cn.
  • # Contributed equally.
PMID: 39103523 DOI: 10.1038/s41422-024-01013-3
Abstract

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.

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