Abstract
Doxorubicin and platinum are widely used in the frontline treatment of osteosarcoma, but resistance to chemotherapy limits its curative effect. Here, we have identified that METTL1 mediated N7-Methyladenosine (m7G) low expressed in osteosarcoma tissues, plays a critical oncogenic role, and enhances osteosarcoma chemosensitivity in osteosarcoma. Mechanistically, AlkAniline-Seq data revealed that Ferritin heavy chain (FTH1), the main component of ferritin, which is crucial for iron homeostasis and the inhibition of lipid peroxidation, is one of the top 10 genes with the most significant change in m7G methylation sites mediated by METTL1 in human osteosarcoma cells. Interestingly, METTL1 significantly increased the expression of FTH1 at the mRNA level but was remarkably suppressed at the protein level. We then identified primary (pri)-miR-26a and pri-miR-98 in the Top 20 m7G-methylated pri-miRNAs with highly conserved species. Further results confirmed that METTL1 enhances cell ferroptosis by targeting FTH1 and primary (pri)-miR-26a, promoting their maturity by enhancing RNA stability dependent on m7G methylation. The increase of mature miR-26a-5p that resulted from METTL1 overexpression could further target FTH1 mRNA and eliminate FTH1 translation efficiency. Moreover, the reduction of FTH1 translation dramatically increases cell ferroptosis and promotes the sensitivity of osteosarcoma cells to chemotherapy drugs. Collectively, our study demonstrates the METTL1/pri-miR-26a/FTH1 axis signaling in osteosarcoma and highlights the functional importance of METTL1 and m7G methylation in the progression and chemotherapy resistance of osteosarcoma, suggesting that reprogramming RNA m7G methylation as a potential and promising strategy for osteosarcoma treatment.
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Change history
28 February 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41388-024-02978-6
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Funding
This work was supported by grants from the National Natural Science Fund of China (82273026, 81972117), the Key R&D Program of Heilongjiang Province (GA23C002), The First Affiliated Hospital of Harbin Medical University Excellent Young Talents Funding (HYD2020JQ0013), the Natural Science Foundation of Heilongjiang Province of China for Outstanding Youth (YQ2020H019), and CAMS Innovation Fund for Medical Sciences (CIFMS, 2020-I2M-5-003), Heilongjiang Innovative Talent Training Fund for Young Teachers (to Y.Y. in 2020).
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M.H., Y.W., and J.X., together with J.P., Z.S., Y.L., W.W., X.L., J.H., Q.L., H.L., and X.H. performed in vitro assays. M.H., Y.W., J.X., A.W., T.L., T.W., G.L., Z.M., and Z.R. contributed to the in vivo animal experiments. L.Y., W.D., and Y.Y. designed experiments and supervised the study. Y.Y., M.H., and Y.W. analyzed and interpreted data. Y.Y. and M.H. wrote the draft, and all of the authors revised and approved the final manuscript.
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Written informed consent was obtained from all participants by the Declaration of Helsinki. All the collection of specimens and animal handling in this study was reviewed and approved by the Medical Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (KY2018-185).
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He, M., Wang, Y., Xie, J. et al. M7G modification of FTH1 and pri-miR-26a regulates ferroptosis and chemotherapy resistance in osteosarcoma. Oncogene 43, 341–353 (2024). https://doi.org/10.1038/s41388-023-02882-5
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DOI: https://doi.org/10.1038/s41388-023-02882-5
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