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M7G modification of FTH1 and pri-miR-26a regulates ferroptosis and chemotherapy resistance in osteosarcoma

Oncogene volume 43, pages 341–353 (2024)Cite this article

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A Correction to this article was published on 28 February 2024

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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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Fig. 1: METTL1 overexpression inhibits osteosarcoma development.
Fig. 2: METTL1 increases the sensitivity of osteosarcoma cells to chemotherapeutic agents.
Fig. 3: METTL1 increases the m7G methylation modification of FTH1 and stabilizes FTH1 mRNA.
Fig. 4: METTL1 decreases FTH1 translation by mediating the maturity of miR-26a.
Fig. 5: METTL1 induces ferroptosis in human osteosarcoma cells.
Fig. 6: miR-26a-5p downregulation abrogates the promoting effect of METTL1 on ferroptosis.
Fig. 7: Fer-1 reversed the inhibition effects of METTL1 on tumor growth in vivo.

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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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Author notes

  1. These authors contributed equally: Mingyu He, Yang Wang, Jiajie Xie.

Authors and Affiliations

  1. National key laboratory of frigid cardiovascular disease, Harbin, China

    Mingyu He, Ao Wang, Tao Li, Tong Wang, Guanghui Li, Ying Liu, Zhongting Mei, Qian Liu, Hong Lei, Xiaoqi He, Weijie Du & Ye Yuan

  2. Department of Pharmacology (The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China

    Mingyu He, Ao Wang, Tao Li, Tong Wang, Guanghui Li, Ying Liu, Zhongting Mei, Qian Liu, Hong Lei, Xiaoqi He & Weijie Du

  3. Department of Pharmacy (The University Key Laboratory of Drug Research, Heilongjiang Province), The Second Affiliated Hospital of Harbin Medical University, Harbin, China

    Yang Wang, Jiajie Xie, Jiaying Pu, Zhihua Shen, Zijing Ren, Jinhuan Hong & Ye Yuan

  4. Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China

    Yang Wang, Jiajie Xie, Jiaying Pu, Zhihua Shen, Zijing Ren, Jinhuan Hong & Ye Yuan

  5. Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Wenbo Wang, Xiaoyan Liu & Lei Yang

  6. Key Laboratory of Hepatosplenic Surgery of Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Wenbo Wang, Xiaoyan Liu & Lei Yang

  7. NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Wenbo Wang, Xiaoyan Liu & Lei Yang

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  1. Mingyu He
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Contributions

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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Correspondence to Ye Yuan or Lei Yang.

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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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