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m6A-driven NAT10 translation facilitates fatty acid metabolic rewiring to suppress ferroptosis and promote ovarian tumorigenesis through enhancing ACOT7 mRNA acetylation

Oncogene volume 43, pages 3498–3516 (2024)Cite this article

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Abstract

RNA epigenetic modifications have been implicated in cancer progression. However, the interplay between distinct RNA modifications and its role in cancer metabolism remain largely unexplored. Our study demonstrates that N-acetyltransferase 10 (NAT10) is notably upregulated in ovarian cancer (OC), correlating with poor patient prognosis. IGF2BP1 enhances the translation of NAT10 mRNA in an m6A-dependent manner in OC cells. NAT10 drives tumorigenesis by mediating N4-acetylcytidine (ac4C) modification of ACOT7 mRNA, thereby augmenting its stability and translation. This NAT10-ACOT7 axis modulates fatty acid metabolism in cancer cells and promotes tumor progression by suppressing ferroptosis. Additionally, our research identifies fludarabine as a small molecule inhibitor targeting NAT10, inhibits the ac4C modification and expression of ACOT7 mRNA. By using cell derived xenograft model and patient derived organoid model, we show that fludarabine effectively suppresses ovarian tumorigenesis. Overall, our study highlights the pivotal role of the NAT10-ACOT7 axis in the malignant cancer progression, underscoring the potential of targeting NAT10-mediated ac4C modification as a viable therapeutic strategy for this disease.

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Fig. 1: m6A activates NAT10 translation in OC cells.
Fig. 2: NAT10 promotes ovarian tumorigenesis through ac4C RNA modification.
Fig. 3: NAT10 mediates ac4C modification and expression of mRNA in OC cells.
Fig. 4: NAT10 promotes the stability and translation of ACOT7 mRNA in an ac4C-dependent manner.
Fig. 5: The critical function of NAT10-ACOT7 axis in OC tumorigenesis and metastasis.
Fig. 6: NAT10 regulates fatty acid metabolism and suppresses ferroptosis through ACOT7.
Fig. 7: NAT10 inhibitor abrogates ac4C modification of ACOT7 mRNA.
Fig. 8: The therapeutic effect of fludarabine on OC.

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Data availability

All datasets generated in this study have been deposited in the Sequenced Read Archive (SRA) database under the accession number PRJNA 1018927. All other raw data can be made available from the corresponding author upon reasonable request.

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Acknowledgements

This work was sponsored by the National Natural Science Foundation of China (82072886, 82273156 and 32101164), the Natural Science Foundation of Chongqing, China (CSTB2022NSCQ-MSX0897) and Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0058).

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  1. These authors contributed equally: Yujiao Liu, Jia Li, Jie Xu.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China

    Yujiao Liu, Jia Li, Jie Xu, Yingfei Long, Yuan Wang, Xiaoyi Liu, Qinglv Wei, Fatao Luo, Fengjiang Qin, Qihua Yi, Yu Yang, Jing Xu, Tao Liu & Ping Yi

  2. Department of Gynecology, Guiyang Maternal and Child Health Care Hospital, Guiyang, 561000, Guizhou, China

    Jia Li

  3. Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China

    Junchi Hu & Yongjun Dang

  4. Department of Pathology, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Qingya Luo

  5. Department of Obstetrics and Gynecology, Chongqing University Fuling Hospital, Chongqing, 408000, China

    Fengjiang Qin

  6. Department of Gynecology, Chongqing University Three Gorges Hospital, Chongqing, 404100, China

    Qihua Yi

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Contributions

PY and TL designed the research. Yujiao Liu, Jia Li, Jie Xu and Yingfei Long performed most experiments and data analysis. QW and QY helped with statistical analysis. YW, XL, JH, QL, FL and FQ conducted part of experiments. YY, YD and Jing Xu helped with experimental data analysis. Yujiao Liu, Jie Xu and TL wrote the manuscript. All authors have read and approved the article.

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Correspondence to Tao Liu or Ping Yi.

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All methods were performed in accordance with the relevant guidelines and regulations. Approval from the Ethical Review Committee of the Third Affiliated Clinical Hospital Institution of Chongqing Medical University (2022-93-01) and the Institutional Review Board of Daping Hospital at Army Medical University (2022-374) was received for the human tissue study, and informed consent was obtained from all patients involved. All animal experiments were approved by the Institutional Animal Care and Use Committee of Chongqing Medical University (No. IACUC-CQMU-2023-0254).

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Liu, Y., Li, J., Xu, J. et al. m6A-driven NAT10 translation facilitates fatty acid metabolic rewiring to suppress ferroptosis and promote ovarian tumorigenesis through enhancing ACOT7 mRNA acetylation. Oncogene 43, 3498–3516 (2024). https://doi.org/10.1038/s41388-024-03185-z

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