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NSUN2 regulates Wnt signaling pathway depending on the m5C RNA modification to promote the progression of hepatocellular carcinoma

Oncogene volume 43, pages 3469–3482 (2024)Cite this article

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Abstract

5-Methylcytosine (m5C) RNA modification is a highly abundant and important epigenetic modification in mammals. As an important RNA m5C methyltransferase, NOP2/Sun-domain family member 2 (NSUN2)-mediated m5C RNA modification plays an important role in the regulation of the biological functions in many cancers. However, little is known about the biological role of NSUN2 in hepatocellular carcinoma (HCC). In this study, we found that the expression of NSUN2 was significantly upregulated in HCC, and the HCC patients with higher expression of NSUN2 had a poorer prognosis than those with lower expression of NSUN2. NSUN2 could affect the tumor immune regulation of HCC in several ways. In vitro and in vivo experiments confirmed that NSUN2 knockdown significantly decreased the abilities of proliferation, colony formation, migration and invasion of HCC cells. The methylated RNA immunoprecipitation-sequencing (MeRIP-seq) showed NSUN2 knockdown significantly affected the abundance, distribution, and composition of m5C RNA modification in HCC cells. Functional enrichment analyses and in vitro experiments suggested that NSUN2 could promote the HCC cells to proliferate, migrate and invade by regulating Wnt signaling pathway. SARS2 were identified via the RNA immunoprecipitation-sequencing (RIP-Seq) and MeRIP-seq as downstream target of NSUN2, which may play an important role in tumor-promoting effect of NSUN2-mediated m5C RNA modification in HCC. In conclusion, NSUN2 promotes HCC progression by regulating Wnt signaling pathway and SARS2 in an m5C-dependent manner.

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Fig. 1: The general features of NSUN2 in HCC based on the TCGA database.
Fig. 2: NSUN2 knockdown inhibits HCC cell proliferation, migration and invasion.
Fig. 3: NSUN2 knockdown inhibits HCC xenograft growth.
Fig. 4: Overview of the landscape of NSUN2-mediated m5C mRNA modification in Huh7 cell.
Fig. 5: The joint analysis of modification levels and transcriptomes in mRNA in HCC.
Fig. 6: NSUN2 knockdown inhibits Wnt signaling pathway in HCC.
Fig. 7: NSUN2 knockdown inhibits HCC progression through Wnt signaling pathway.
Fig. 8: RIP-seq data analysis of HCC after NSUN2 knockdown.

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Data availability

All data related to this study can be obtained from the corresponding authors upon reasonable request. The m5C MeRIP-seq data are available in GEO database (ID: GSE228973), the single cell transcriptome sequencing data are available in GSE149614 from GEO database, and other RNA-seq data are available in TCGA database (TCGA-LIHC).

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Acknowledgements

This work was supported by the China Postdoctoral Science Foundation (2023M743200 and 2024T170826), the Postdoctoral Fellowship Program of CPSF (GZC20232425), the Science and Technology Research Program of Henan Province (242102311163), the Henan Medical Science and Technology Joint Building Program (LHGJ20230160), and the Henan Sunshine Medical Health Development Foundation iGanDan Project (HKP2023001 and HKP2023006).

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  1. These authors contributed equally: Huiwu Xing, Xinyu Gu.

Authors and Affiliations

  1. Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Huiwu Xing

  2. Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China

    Xinyu Gu

  3. Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Yingru Liu, Lixia Xu & Chen Xue

  4. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Yuting He

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Contributions

CX and YH conceptualized and supervised this study, HX and XG participated in the overall experiments and wrote the draft. YL prepared figures. LX collected and analyzed data. All authors contributed to the article and approved the submitted version.

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Correspondence to Yuting He or Chen Xue.

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All methods used in this study were performed in accordance with the relevant guidelines and regulations. All animal experiments in this study were carried out in accordance with the regulations of Experimental Animal Use and Welfare Committee of Zhengzhou University (approval number: ZZU-LAC2024060416).

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Xing, H., Gu, X., Liu, Y. et al. NSUN2 regulates Wnt signaling pathway depending on the m5C RNA modification to promote the progression of hepatocellular carcinoma. Oncogene 43, 3469–3482 (2024). https://doi.org/10.1038/s41388-024-03184-0

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  • DOI: https://doi.org/10.1038/s41388-024-03184-0

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