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

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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Publication Details

Journal
Cell Research
Published
2024-08-05
DOI
https://doi.org/10.1038/s41422-024-01013-3
Citations
14
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
3.27

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article

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

Bin Xiang, Kehao Zhao, Jinkai Wan, Natasha Flores et al.
14 citations
Cell Research
RNA modifications and cancer
3.27
article

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

Bin Xiang, Kehao Zhao, Jinkai Wan, Natasha Flores, Chenxi He, Xinghao Wang, Xiang Li, Jingdong Cheng, Bisi Miao, Jun Hu, Xinyi Xu, Zhennan Shi, Shenghui Xing, Lijian Feng, Yanyan Yu, Yuanhui Mao, Paweł K. Mazur, Jiajia Chen, Kun Chen, Jiabin Cai, Ling Ge, Jia Fan, Jian Zhou, En Li, Zhihui Liang, Fei Lan, Ruoxin Wang, Lingnan Ren, Shengnan Liu, Jibo Wu
article en
14 citations

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.

Cell ResearchVol. 34(9)
The University of Texas MD Anderson Cancer Center (US), Fudan University (CN), Novartis (China) (CN), Minhang District Central Hospital (CN), Zhongshan Hospital (CN), Ministry of Science and Technology (LA), Second Affiliated Hospital of Zhejiang University (CN)
National Natural Science Foundation of China, Fudan University, Natural Science Foundation of Fujian Province, National Postdoctoral Program for Innovative Talents
Good health and well-being
Openalex Percentile: Top 7%
RNA modifications and cancer
3.27
DOIOpen Access PDFOpenAlex
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