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The m6A Reader YTHDC2 Suppresses Lung Adenocarcinoma Tumorigenesis by Destabilizing MRPL12

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Abstract

N6-methyladenosine (m6A) is the most common posttranscriptional RNA modification and plays significant roles in physiological and pathological progression. Here, we probed the functions and mechanism of the m6A reader YTH domain containing 2 (YTHDC2) in Lung Adenocarcinoma (LUAD) tumorigenesis. Levels of genes and proteins of YTHDC2 and Mitochondrial ribosomal protein L7/L12 (MRPL12) were assayed by quantitative real-time polymerase chain reaction, western blotting and Immunohistochemistry (IHC) analyses. In vitro analysis was conducted using 5-ethynyl-2′-deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays, respectively. In vivo assay was performed by using the mouse lung adenocarcinoma model. The methylated RNA immunoprecipitation (MeRIP) assay was used to detect the m6A modification profile of MRPL12 mRNA. YTHDC2 was lowly expressed in lung adenocarcinoma tissues and cells. Overexpression of YTHDC2 suppressed the proliferation, invasion and migration of lung adenocarcinoma cells, but induced cell apoptosis. As expected, forced expression of YTHDC2 hindered lung adenocarcinoma tumor growth in vivo. Mechanistically, YTHDC2 preferentially bound to m6A-modified MRPL12 mRNA and destabilized its expression. MRPL12 was highly expressed in lung adenocarcinoma tissues and cells, and MRPL12 silencing repressed the growth and mobility of lung adenocarcinoma cells. Moreover, MRPL12 upregulation attenuated the anticancer activity of YTHDC2 in lung adenocarcinoma cells. In vivo assay also showed YTHDC2 suppressed tumor growth in the lung adenocarcinoma mouse model via downregulating MRPL12. The m6A reader YTHDC2 repressed lung adenocarcinoma tumorigenesis by destabilizing MRPL12 in an m6A-dependent manner.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Oncology, Xuchang Central Hospital, No. 666, Wenxuan Street, Dongcheng District, Xuchang, 461000, China

    Yingchuan Sun, Pengyuan Wang & Jianmin Huang

  2. The Medical College of Xuchang University, Xuchang, 461000, China

    Yanyan Liu & Lin Chang

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  1. Yingchuan Sun
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  2. Yanyan Liu
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  4. Lin Chang
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  5. Jianmin Huang
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Contributions

YS and YL: designed and supervised the study, conducted the experiments and drafted the manuscript. PW: collected and analyzed the data. LC: contributed the methodology and prepared the figures. JH: operated the software and edited the manuscript. All authors reviewed the manuscript.

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Correspondence to Yingchuan Sun.

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The authors declare that they have no conflict of interest.

Ethical Approval

This study was authorized by the Ethics Committee of Xuchang Central Hospital (approval number: 2023-01-002), and written informed consent was collected from all patients. The protocols of animal experiments were approved by the ethics committee of Xuchang Central Hospital (approval number: 2023-01-003).

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12033_2023_1002_MOESM1_ESM.tif

Supplementary file1 (TIF 206 KB) The effects of YTHDC2 silencing on the expression of 8 top elevated genes. qRT-PCR analysis for the expression of 8 top elevated genes that were negatively correlated with YTHDC2 in the LinkedOmics database in A549 cells after YTHDC2 knockdown

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Sun, Y., Liu, Y., Wang, P. et al. The m6A Reader YTHDC2 Suppresses Lung Adenocarcinoma Tumorigenesis by Destabilizing MRPL12. Mol Biotechnol 66, 1051–1061 (2024). https://doi.org/10.1007/s12033-023-01002-8

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  • DOI: https://doi.org/10.1007/s12033-023-01002-8

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