Abstract
Protein arginine methyltransferase 2 (PRMT2) is involved in several biological processes via histone methylation and transcriptional regulation. Although PRMT2 has been reported to affect breast cancer and glioblastoma progression, its role in renal cell cancer (RCC) remains unclear. Here, we found that PRMT2 was upregulated in primary RCC and RCC cell lines. We demonstrated that PRMT2 overexpression promoted RCC cell proliferation and motility both in vitro and in vivo. Moreover, we revealed that PRMT2-mediated H3R8 asymmetric dimethylation (H3R8me2a) was enriched in the WNT5A promoter region and enhanced WNT5A transcriptional expression, leading to activation of Wnt signaling and malignant progression of RCC. Finally, we confirmed that high PRMT2 and WNT5A expression was strongly correlated with poor clinicopathological characteristics and poor overall survival in RCC patient tissues. Our findings indicate that PRMT2 and WNT5A may be promising predictive diagnostic biomarkers for RCC metastasis. Our study also suggests that PRMT2 is a novel therapeutic target in patients with RCC.
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Introduction
Renal cell carcinoma (RCC) is the third most common urological cancer with an increasing incidence [1]. As one of the most treatment-resistant tumors, there is no effective treatment for RCC after metastasis [2]. Consequently, new indicators for evaluating the probability of metastasis and effective therapeutic targets for therapeutic options are urgently needed in patients with metastatic RCC.
Protein arginine methyltransferases (PRMTs) catalyze arginine methylation of histones and nonhistone proteins [3, 4]. PRMTs family members (PRMT1–9) can result in three types of methylarginines: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). The PRMTs family members are sorted to three types according to the type of methylarginines: type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) mediating MMA and ADMA modification, type II (PRMT5 and PRMT9) mediating MMA and SDMA; type III (PRMT7) only mediating MMA modification. Previous studies have demonstrated that arginine methylation of histones regulates gene transcription and H4 histone stability [ Data supporting the findings of this study are available from the corresponding author upon reasonable request. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization. Genes Dev. 2017;31:916–26. We thank Professor Wuhan **ao (Institute of Hydrobiology, Chinese Academy of Sciences) for kindly providing the myc-PRMT2 plasmid. This work was supported by grants from the National Natural Science Foundation of China (82173060), Outstanding Youth Foundation of Jiangsu Province (BK20200046), Excellent Youth Foundation of Jiangsu Province, China (BK20220119), Major Project of the University Natural Science Foundation of Jiangsu Province, China (22KJA310006), Qinglan Project of Jiangsu, and Postgraduate Research and Practice Innovation Project of Jiangsu Province (KYCX21_2669). Study conception and experimental design, data collection and analysis, and paper writing: HL, CC, and Zhongwei Li; collection and analysis of data: HY, SM, Zhongwei Li, PW, LJ, Zhen Li, QG, and SC; study conception, design, and supervision: HL, JZ, JB, and Zhongwei Li; supervision, paper writing, and final approval of the paper: HL, Zhongwei Li, JZ, and JB. The authors declare no competing interests. This study was conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from all subjects. Ethical approval for the study was obtained from the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University. Ethical approval for animal experiments was provided by the Institutional Animal Care and Use Committee of Xuzhou Medical University. Not applicable. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Edited by Dr Satoshi Inoue Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Li, Z., Chen, C., Yong, H. et al. PRMT2 promotes RCC tumorigenesis and metastasis via enhancing WNT5A transcriptional expression.
Cell Death Dis 14, 322 (2023). https://doi.org/10.1038/s41419-023-05837-6 Received: Revised: Accepted: Published: DOI: https://doi.org/10.1038/s41419-023-05837-6 Cell Death & Disease (2024) Cell Death Discovery (2024) Molecular Neurobiology (2024)Data availability
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