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Genetics and Genomics

YTHDF2-mediated FGF14-AS2 decay promotes osteolytic metastasis of breast cancer by enhancing RUNX2 mRNA translation

British Journal of Cancer volume 127, pages 2141–2153 (2022)Cite this article

Subjects

Abstract

Background

LncRNA FGF14-AS2 is a critical suppressor in breast cancer (BCa) metastasis. However, whether FGF14-AS2 plays a role in the bone metastasis of BCa remains unknown.

Methods

TRAP assay and intratibial injection were carried out to evaluate the role of FGF14-AS2 in BCa bone metastasis in vitro and in vivo. Polyribosome profiling was done to examine the translation level. RNA pulldown combined with LC/MS was performed to identify the lncRNA-binding partner, RIP, dual-luciferase assay, and Co-IP assays as well to testify these physical interactions. The prognostic value of FGF14-AS2 expression level in BCa patients was analysed using Kaplan–Meier Plotter.

Results

We found that FGF14-AS2 suppresses osteoclast differentiation and osteolytic metastasis of BCa. Mechanistically, FGF14-AS2 suppresses the translation of RUNX2 by inhibiting the assembly of eIF4E/eIF4G complex and the phosphorylation of eIF4E, thereby reducing the transcription of RANKL, an essential regulator of osteoclast differentiation. Moreover, FGF14-AS2 is downregulated by YTHDF2-mediated RNA degradation in an m6A-dependent manner. Clinically, patients with high YTHDF2 and low FGF14-AS2 expression levels showed worse distant metastasis-free survival (DMFS).

Conclusions

FGF14-AS2 plays a crucial role in osteolytic metastasis, and may serve as a promising prognostic biomarker and therapeutic target for BCa bone metastasis.

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Fig. 1: FGF14-AS2 suppresses breast cancer osteolytic metastasis.
Fig. 2: FGF14-AS2 suppresses osteolytic metastasis via the RUNX2/RANKL axis.
Fig. 3: FGF14-AS2 inhibits RUNX2 translation.
Fig. 4: FGF14-AS2 interferes with eIF4E/eIF4G complex formation.
Fig. 5: FGF14-AS2 inhibits eIF4E phosphorylation via the EIF2AK2/p38 signalling pathway.
Fig. 6: YTHDF2 mediates the downregulation of FGF14-AS2.

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Data availability

All the data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81872389, 81570804 and 82072484); the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Key Project of Science; the Major Projects of Science and Technology Development Fund of Nanjing Medical University (No. NMUD2019004).

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Authors and Affiliations

  1. Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China

    Ming Zhang, Yucui Jin, Que Zheng, Mengying Xing, Yuting Tang, Yunfei Ma, Lingyun Li, Bing Yao & Changyan Ma

  2. Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, 211166, Nanjing, P.R. China

    Ming Zhang & Changyan Ma

  3. Division of Breast Surgery, the First Affiliated Hospital with Nanjing Medical University, Guangzhou Road 300, 210029, Nanjing, Jiangsu Province, P.R. China

    Jue Wang

  4. Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, 210029, Nanjing, Jiangsu Province, P.R. China

    Hao Wu

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Contributions

MZ, MX and YT performed the experiments. WJ provided the clinical samples. MZ performed the statistical analysis. YM and YJ performed the bioinformatic analyses. HW and QZ reviewed the data. LL, BY, YJ and CM designed the research and drafted the manuscript.

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Correspondence to Changyan Ma.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Nanjing Medical University (Approval number: 2018-487) and with the Declaration of Helsinki and its later amendments or comparable ethical standards, and all patients provided written informed consent.

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Zhang, M., Wang, J., Jin, Y. et al. YTHDF2-mediated FGF14-AS2 decay promotes osteolytic metastasis of breast cancer by enhancing RUNX2 mRNA translation. Br J Cancer 127, 2141–2153 (2022). https://doi.org/10.1038/s41416-022-02006-y

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