Volume 34, No 9, Sep 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 9, September 2024: 648-660   |  Open Access

ORIGINAL ARTICLES

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

Bisi Miao^1,† , Ling Ge^1,† , Chenxi He^1,† , Xinghao Wang^2,† , Jibo Wu^3,† , Xiang Li⁴ , Kun Chen¹ , Jinkai Wan¹ , Shenghui Xing¹ , Lingnan Ren¹ , Zhennan Shi¹ , Shengnan Liu² , Yajun Hu¹ , Jiajia Chen¹ , Yanyan Yu² , Lijian Feng² , Natasha M. Flores³ , Zhihui Liang¹ , Xinyi Xu¹ , Ruoxin Wang¹ , Jian Zhou¹ , Jia Fan¹ , Bin Xiang² , En Li² , Yuanhui Mao⁵ , Jingdong Cheng⁴ , Kehao Zhao² , Pawel K. Mazur^3,* , Jiabin Cai^1,* , Fei Lan^1,*

¹1 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
²China Novartis Institutes for BioMedical Research, Shanghai, China
³Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
⁴Minhang Hospital & Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, China
⁵Department of Neurology of The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
^†These authors contributed equally: Bisi Miao, Ling Ge, Chenxi He, Xinghao Wang, Jibo Wu
Correspondence: Pawel K. Mazur(pkmazur@mdanderson.org)Jiabin Cai(cai.jiabin@zs-hospital.sh.cn)Fei Lan(fei_lan@fudan.edu.cn)

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.

https://doi.org/10.1038/s41422-024-01013-3

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