SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression

Author:

Zhou Zhenyu12,Chen Zheng3,Zhou Qianlei24,Meng Shiyu25,Shi Juanyi12,Mui Sintim12,Jiang Hai6ORCID,Lin Jianhong12,He Gui7,Li Wenbin28,Zhang Jianlong12,Wang Jie12,He Chuanchao12,Yan Yongcong12,Xiao Zhiyu12ORCID

Affiliation:

1. Department of Hepatobiliary Surgery, Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

3. Department of Gastrointestinal Surgery The Fifth Affiliated Hospital of Sun Yat‐Sen University Zhuhai Guangdong China

4. Department of Thyroid Surgery, Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

5. Department of Anesthesiology, Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

6. Department of General Surgery The First Affiliated Hospital of Nanchang University Nanchang China

7. Cellular & Molecular Diagnostics Center, Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

8. Department of Pancreaticobiliary Surgery, Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou China

Abstract

AbstractBoth lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well‐known arginine methyltransferase, was identified as a SMYD4‐binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E‐cadherin, RBL2, and miR‐29b‐1‐5p. Moreover, miR‐29b‐1‐5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor in vitro and in vivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4‐PRMT5 axis as a potential therapeutic target for the treatment of HCC.

Funder

Guangdong Provincial Department of Science and Technology

National Natural Science Foundation of China

Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University

Publisher

Wiley

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Genetic Alterations of SMYD4 in Solid Tumors Using Integrative Multi-Platform Analysis;International Journal of Molecular Sciences;2024-05-31

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